CN1882551A - Hexahydrodiazepinones as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes - Google Patents

Hexahydrodiazepinones as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes Download PDF

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CN1882551A
CN1882551A CNA2004800221846A CN200480022184A CN1882551A CN 1882551 A CN1882551 A CN 1882551A CN A2004800221846 A CNA2004800221846 A CN A2004800221846A CN 200480022184 A CN200480022184 A CN 200480022184A CN 1882551 A CN1882551 A CN 1882551A
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unsubstituted
halogen
alkyl
alkoxyl group
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梁贵柏
冯丹青
A·E·韦伯
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Merck and Co Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The present invention is directed to hexahydrodiazepinone compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ('DPP-IV inhibitors') and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Description

Be used for the treatment of or six hydrogen diaza azepines ketone of the dipeptidyl peptidase-IV enzyme inhibitors of prevent diabetes
Technical field
The present invention relates to six new hydrogen diaza azepines ketone (hexahydrodiazepinone) compounds, they are dipeptidyl peptidase-IV enzyme inhibitors (" DPP-IV inhibitor "), they are used for the treatment of or prevent wherein to comprise the disease of dipeptidyl peptidase-IV enzyme, for example diabetes, especially type ii diabetes.The invention still further relates to the pharmaceutical composition that contains these compounds and these compounds and composition and wherein comprise purposes in such disease of dipeptidyl peptidase-IV enzyme in prevention or treatment.
Background technology
The disease that diabetes are caused by multiple paathogenic factor, by under the empty stomach state or in oral glucose tolerance test behind administration glucose the high-content of plasma glucose or hyperglycemia characterize.Lasting or uncontrolled hyperglycemia is with increase relevant with too early M ﹠ M.Abnormal glucose running balance also directly with indirectly with the lipid change, that lipoprotein is relevant with the apolipoproteins metabolism is relevant with the Hemodynamics disease with other metabolism.Therefore, the type ii diabetes patient especially has the risk of the great vessels and the microvascular complication of increase, for example coronary heart disease, apoplexy, peripheral vascular disease, hypertension, ephrosis, neuropathy and retinopathy.Therefore, glucose running balance, lipid metabolism and hypertensive treatment be controlled at diabetes Clinical Processing and the treatment in be crucial.
The diabetes that have two kinds of common understanding forms: in the diabetes (IDDM) of type i diabetes or insulin-dependent, the patient produces on a small quantity or does not produce Regular Insulin, the utilization of hormone regulation glucose, in type ii diabetes or noninsulin dependent diabetes (NIDDM), the patient has plasma insulin content usually, they compare with the ND plasma insulin content identical or even raise, yet these patients develop into Regular Insulin usually at main insulin sensitivity tissue, be muscle, in liver and the fatty tissue to the tolerance of the effect of stimulation of glucose and lipid metabolism, and plasma insulin content, even when raising, also be not enough to overcome significant insulin resistance.
The insulin resistance master is the not enough quantity of insulin receptor except for, but since at present the back insulin receptor of understanding not yet in conjunction with effect.Insulin resistance response cause insufficient Regular Insulin activation of glucose uptake, oxidation and storage in muscle and in fatty tissue in lipolysis and the liver glucose produce and the inappropriate Regular Insulin of excretory suppresses.
Method at many year unaltered basically present treatment type ii diabetes has the understanding restriction, though body exercise and reduction calorie comprise absorption and will obviously improve diabetic symptom, treatment is non-constant according to this, because the mode of life of the custom of Que Dinging and excessive food consumption, especially contain the food of high-content saturated fatty.Increase plasma insulin content by administration sulfonylurea (for example tolbutamide and Glipizide) or meglitinide; their stimulating pancreas beta cells can cause the enough height of insulin concentration to stimulate the insulin resistance tissue with the more Regular Insulin of secretion and/or when sulfonylurea or meglitinide become invalid by insulin injection.Yet administration Regular Insulin or insulin secretagogue (sulfonylurea or meglitinide) can cause dangerous low plasma glucose content, even can occur increasing the insulin resistance of content owing to higher Regular Insulin blood plasma content.Biguanides increases insulin sensitivity, produces some correction of hyperglycemia, yet, many biguanides, phenformin and metformin, cause lactose too much, gastric disorder causing nausea and diarrhoea.Metformin has low side effect, the designated type ii diabetes that is used for the treatment of usually than phenformin.
Glitazone (being 5-benzyl thiazolidine-2, the 4-diketone) is the classes of compounds that effectively alleviates the many symptoms of type ii diabetes that has of advising in recent years.These medicines obviously are increased in the insulin sensitivity in muscle, liver and the fatty tissue in some type ii diabetes animal models, cause high glucose plasma content partially or completely to be proofreaied and correct, and do not occur hypoglycemia basically.The glitazone of listing is a peroxisome hyperplasia activated receptor (PPAR) at present, mainly is the agonist of PPAR-γ hypotype.PPAR-γ agonism is considered to cause the reason of the insulin sensitivityization of using the viewed improvement of glitazone usually.The new PPAR agonist that test is used for the treatment of type ii diabetes is PPAR α, γ and δ subtype agonist or its combination, but is being different (being that they are not thiazolidinediones) with glitazone chemically in many cases.To some glitazone, for example severe side effect (for example hepatotoxicity) appears in troglitazone.
Other method of treatment disease has been introduced new biochemical method recently or has still been comprised the treatment of using alpha-glucosidase inhibitor (for example acarbose) and Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor in exploitation still under study for action.
The compound that is dipeptidyl peptidase-IV (" DPP-IV " or " DP-IV ") enzyme inhibitors is also at the medicine of research as effective treatment diabetes, especially type ii diabetes.Referring to for example WO97/40832, WO98/19998, US5,939,560, Bioore.Med.Chem.Lett., 6:1163-1166 (1996) and Bioorg.Med.Chem.Lett., 6:2745-2748 (1996).The validity of DPP-IV inhibitor in the treatment type ii diabetes is based on and is easy to the inactivation hyperglycemic-glycogenolytic factor in the DPP-IV body, as the fact of peptide-1 (GLP-1) and gastrin inhibitory polypeptide (GIP).GLP-1 and GIP are incretins, produce when food consumption, and incretin stimulates the product of Regular Insulin.The inactivation that the inhibition of DPP-IV causes incretin to reduce, thus cause incretin in the effect that stimulates the increase aspect pancreas generation Regular Insulin.Thereby DPP-IV suppresses to produce the serum insulin content that increases content.Advantageously, because incretin is only produced by health when food consumption, DPP-IV suppresses not to be expected at the unsuitable time, for example increases insulin content between having meal, and this can cause too low blood sugar (hypoglycemia).Therefore increase Regular Insulin is expected in the inhibition of DPP-IV, and does not increase the risk of hypoglycemia, and this is dangerous side-effects relevant when using insulin secretagogue.
As this paper discussion, the DPP-IV inhibitor also has other treatment to be used, and the DPP-IV inhibitor is not also fully studied so far, especially the application except that diabetes.Need new compound, thereby but the DPP-IV inhibitor saponin of improving is used for the treatment of diabetes and other disease of potential and symptom.The treatment effectiveness that is used for the treatment of the DPP-IV inhibitor of type ii diabetes is existed by D.J.Drucker Exp.Opin.Invest.Drugs, 12:87-100 (2003) and exist by K.Augustyns etc. Exp.Opin.Ther.Patents, discuss among the 13:499-510 (2003).
Summary of the invention
The present invention relates to six new hydrogen diaza azepines ketone compounds, they are dipeptidyl peptidase-IV enzyme inhibitors (" DPP-IV inhibitor "), they are used for the treatment of or prevent wherein to comprise the disease of dipeptidyl peptidase-IV enzyme, for example diabetes, especially type ii diabetes.The invention still further relates to the pharmaceutical composition that contains these compounds and these compounds and composition and wherein comprise purposes in such disease of dipeptidyl peptidase-IV enzyme in prevention or treatment.
Detailed Description Of The Invention
The present invention relates to six hydrogen diaza azepines ketone compounds as dipeptidyl peptidase-iv inhibitor, compound of the present invention is described by structural formula I:
Or its pharmaceutically useful salt; Wherein
N is respectively 0,1 or 2;
Ar is by 1-5 R 3The phenyl that substituting group replaces;
R 1Be selected from following group:
H；
C 1-10Alkyl, wherein alkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, CN, hydroxyl, R respectively by 1-5 2, OR 2, NHSO 2R 2, NR 2SO 2R 2, SO 2R 2, CO 2H and C 1-6The substituting group of alkoxy carbonyl replaces;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heterocyclic radical, wherein heterocyclic radical is unsubstituted or is selected from oxo, hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-6The substituting group of alkyl replaces, C 1-6Alkyl is unsubstituted or is replaced by 1-5 halogen;
Each R 3Be selected from following group respectively:
H；
Halogen;
Cyano group;
Hydroxyl;
C 1-6Alkyl is unsubstituted or replaced by 1-5 halogen;
C 1-6Alkoxyl group is unsubstituted or replaced by 1-5 halogen;
Carboxyl;
Alkoxy carbonyl;
Amino;
NHR 2；
NR 2R 2；
NHSO 2R 2；
NR 2SO 2R 2；
NHCOR 2；
NR 2COR 2；
NHCO 2R 2；
NR 2CO 2R 2；
SO 2R 2；
SO 2NH 2；
SO 2NHR 2With
SO 2NR 2R 2；
Each R 2Be respectively C 1-6Alkyl, it is unsubstituted or is selected from halogen, CO respectively by 1-5 2H and C 1-6The substituting group of alkoxy carbonyl replaces;
R 4, R 6And R 10Be selected from following group respectively:
H；
Cyano group;
Carboxyl;
C 1-6Alkoxy carbonyl;
C 1-10Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heterocyclic radical, wherein heterocyclic radical is unsubstituted or is selected from oxo, hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) nCONR 12R 13, R wherein 12And R 13Be selected from H, tetrazyl, thiazolyl, (CH respectively 2) n-phenyl, (CH 2) n-C 3-6Cycloalkyl and C 1-6Alkyl, wherein alkyl is unsubstituted or is replaced by 1-5 halogen, wherein phenyl and cycloalkyl are unsubstituted or are selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement or R 12And R 13Be connected to form heterocycle with the nitrogen-atoms that links to each other with them, it is selected from azetidine, tetramethyleneimine, piperidines, piperazine and morpholine, and wherein said heterocycle is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen;
R 8Be to be selected from halogen, hydroxyl and R 4Group;
R 5, R 7And R 11Be selected from H or C respectively 1-6Alkyl; Or R wherein 7And R 1With and R 1The nitrogen-atoms that links to each other is connected to form heterocycle together, and it is selected from azetidine, tetramethyleneimine and piperidines, and wherein said heterocycle is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; And R 9Be to be selected from H, hydroxyl, halogen or C 1-6The group of alkyl;
Its prerequisite is R 6, R 7, R 8And R 9Be not H one of at least.
In an embodiment of The compounds of this invention, have described R configuration suc as formula Ia with the * marked carbon atoms:
Figure A20048002218400171
Wherein Ar, R 1, R 4, R 5, R 6, R 7, R 8, R 9, R 10And R 11Be as defined herein.
In second embodiment of compound of the present invention,
R 3Be the group that is selected from H, fluorine, chlorine, bromine, trifluoromethyl and methyl, in a kind of this embodiment, R 3Be the group that is selected from H, fluorine and chlorine, in this type of subclass, R 3Be H or fluorine.
In the 3rd embodiment of The compounds of this invention, R 1Be selected from following group:
H；
C 1-6Alkyl, wherein alkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement; With
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
In a kind of this embodiment of compound of the present invention, R 1Be to be selected from following group:
H；
Methyl; With
Cyclopropyl.
In such subclass, R 1Be H.
In the 4th embodiment of compound of the present invention, R 4Be to be selected from following group:
H；
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
In a kind of this embodiment, R 4Be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph)。
In the 5th embodiment of compound of the present invention, R 6Be to be selected from following group:
H；
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
In a class of this embodiment, R 6Be to be selected from following group:
H；
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
In the subclass of this kind, R 6Be selected from following group:
H；
CH 3；
CH 2CH 3；
CF 3；
CH 2Ph; With
CH 2(2-F-Ph)。
In the 6th embodiment of The compounds of this invention, R 8Be to be selected from following group:
H；
Hydroxyl;
Halogen; With
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement.
In the kind of this embodiment, R 8Be H.
In the 7th embodiment of The compounds of this invention, R 10Be to be selected from following group:
H; With
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement.
In the kind of this embodiment, R 10Be H.
In the 8th embodiment of The compounds of this invention, R 5, R 7And R 11Be selected from H and methyl respectively.
In the kind of this embodiment, R 5, R 7And R 11Be H.
In the 9th embodiment of the present invention, R 9Be selected from H, halogen and methyl.
In a kind of this embodiment, R 9Be H.
In other kind of this embodiment, R 9Be methyl and R 5, R 7, R 8, R 10And R 11Be H.In the subclass of this kind, R 4Be to be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph)。
In the tenth embodiment of The compounds of this invention, R 5, R 7, R 8, R 9, R 10And R 11Be H, its prerequisite is R 6Not H.In the subclass of this embodiment, R 4Be to be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph); With
R 6Be to be selected from following group:
CH 3；
CH 2CH 3；
CF 3；
CH 2Ph; With
CH 2(2-F-Ph)。
In the subclass of this kind, R 1Be H.
In the subclass of this subclass, have the stereochemistry of in formula Ib, representing with the three-dimensional carbon atom of * * and * * * mark:
In the 11 embodiment of The compounds of this invention, R 7And R 1With and R 1The nitrogen-atoms that links to each other is connected to form heterocycle together, and it is selected from azetidine, tetramethyleneimine and piperidines, and wherein said heterocycle is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement.
In a kind of this embodiment, R 7And R 1With and R 1The nitrogen-atoms that links to each other is connected to form pyrrolidine ring together.In such subclass, R 4Be to be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph)。
Be the illustrative of the compound of the present invention of dipeptidyl peptidase-iv inhibitor, unrestricted example is as follows:
Or its pharmaceutically useful salt.
When being used for this paper, applicable as giving a definition.
" alkyl " and have before stop other group of " alkane ", be meant carbochain as alkoxyl group and alkyloyl, they can be straight or branched or its combination, unless carbochain has definition in addition.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season and the tertiary butyl, amyl group, hexyl, heptyl, octyl group, decyl etc.When the number that specifies carbon atom allows, C for example 3-10, the term alkyl also comprise cycloalkyl and with cycloalkyl structure bonded straight or branched alkyl chain.When not specifying carbonatoms, be meant C 1-6
" cycloalkyl " is the subclass of alkyl, is meant the saturated carbon ring that contains the particular carbon atom number.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.Cycloalkyl is normally monocyclic, except as otherwise noted.Cycloalkyl is saturated, except as otherwise noted.
Term " alkoxyl group " is meant the straight or branched alcoholate (C for example of particular carbon atom number 1-10Alkoxyl group) or any number in this scope [being methoxyl group (MeO-), oxyethyl group, isopropoxy etc.].
Term " alkylthio " is meant the straight or branched alkyl sulfur compounds (C for example of particular carbon atom number 1-10Alkylthio) or any number in this scope [being methylthio group (MeS-), ethylmercapto group, iprotiazem base etc.].
Term " alkylamino " is meant the straight or branched alkylamine (C for example of particular carbon atom number 1-6Alkylamino) or any number in this scope [being methylamino-, ethylamino, isopropylamino, tertiary butyl amino etc.].
Term " alkyl sulphonyl " is meant the straight or branched alkyl sulfone (C for example of particular carbon atom number 1-6Alkyl sulphonyl) or any number in this scope [be methyl sulphonyl (MeSO 2-), ethylsulfonyl, sec.-propyl alkylsulfonyl etc.].
Term " alkoxy carbonyl " is meant the straight or branched ester (C for example of the carboxylic acid derivative of the present invention of particular carbon atom number 1-6Alkoxy carbonyl) or any number in this scope [being methoxycarbonyl (MeOCO-), ethoxy carbonyl or butoxy carbonyl].
" aryl " is meant list or the fragrant ring system of many cyclophanes that contains carboatomic ring atom, and preferred aryl groups is monocycle or dicyclo 6-10 unit aromatic ring.Phenyl and naphthyl are preferred aryl groups, and most preferably aryl is a phenyl.
" heterocycle " and " heterocyclic radical " is meant and contains heteroatomic saturated or unsaturated non-aromatic ring or the ring system that at least one is selected from O, S and N, and it also contains the oxidised form of sulphur, i.e. SO and SO 2The heterocyclic example comprises tetrahydrofuran (THF) (THF), dihydrofuran, 1,4-two  alkane, morpholine, 1,4-dithiane, piperazine, piperidines, 1,3-dioxolane, imidazolidine, tetrahydroglyoxaline, pyrroline, tetramethyleneimine, tetrahydropyrans, dihydropyrane, oxathiolane, dithiolane, 1,3-two  alkane, 1,3-dithiane, oxa-thiophene alkane, thiomorpholine etc.
" heteroaryl " is meant fragrance or part aromatic heterocycle, and it contains at least one ring hetero atom that is selected from O, S and N.Therefore, heteroaryl comprises and condensing in other kind ring, for example the heterocyclic heteroaryl of aryl, cycloalkyl and non-fragrance.The example of heteroaryl comprises: pyrryl, different  azoles base, isothiazolyl, pyrazolyl, pyridyl, the 2-oxo-(1H)-pyridyl (2-hydroxyl-pyridyl),  azoles base, 1,2,4- di azoly, 1,3,4- di azoly, thiadiazolyl group, thiazolyl, imidazolyl, triazolyl, tetrazyl, furyl, triazinyl, thienyl, pyrimidyl, pyrazinyl, benzisoxa  azoles base, the benzoxazol base, benzothiazolyl, the diazosulfide base, dihydro benzo furyl, indolinyl, pyridazinyl, indazolyl, pseudoindoyl, the dihydrobenzo thienyl, the indolizine base, cinnolinyl, phthalazinyl, quinazolyl, naphthyridinyl, carbazyl, the benzo dioxolanyl, quinoxalinyl, purine radicals, the furazan base, different benzyl furyl, benzimidazolyl-, benzofuryl, benzothienyl, quinolyl, indyl, isoquinolyl, dibenzofuran group, imidazo [1,2-a] pyridyl, [1,2, the 4-triazolo] [4,3-a] pyridyl, pyrazolo [1,5-a] pyridyl, [1,2, the 4-triazolo] [1,5-a] pyridyl, 2-oxo-1,3-benzoxazol base, 4-oxo-3H-quinazolyl, 3-oxo-[1,2,4] triazolo [4,3-a]-the 2H-pyridyl, 5-oxo-[1,2,4]-4H- di azoly, 2-oxo-[1,3,4]-3H- di azoly, 2-oxo-1,3-dihydro-2H-imidazolyl, 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl etc.For heterocyclic radical and heteroaryl, comprise the ring and the ring system that contain 3-15 atom, comprise 1-3 ring.
" halogen " is meant fluorine, chlorine, bromine and iodine, and chlorine and fluorine are normally preferred, and fluorine is most preferred (CF for example when halogen replaces on alkyl or alkoxyl group 3O and CF 3CH 2O).
Compound of the present invention can contain one or more asymmetric centers, therefore can produce racemic modification and racemic mixture, single enantiomorph, non-enantiomer mixture and one diastereomer.The compounds of this invention has the asymmetric center of using the * marked carbon atoms and use *, * * and * * * marked carbon atoms in formula Ia in formula Ib, and additional asymmetric center can exist according to the character of different substituents in the molecule.Each this asymmetric center will independent two kinds of optically active isomers, and all possible optically active isomer, non-enantiomer mixture and pure or partial purification compound include within the scope of the invention, and purpose of the present invention comprises all isomeric form of these compounds.
Some compound described herein contains olefinic double bond, except as otherwise noted, is meant to comprise E and Z geometrical isomer.
Can there be tautomer in some compound described herein, they have because the difference that the hydrogen of one or more pairs of key conversion generations connects, keto-enol tautomerism body for example, one tautomer and their mixture are included in the compound of the present invention.
Formula I has shown the structure that does not have preferred stereochemical classes of compounds, formula Ia is presented at the preferred stereochemistry on the carbon atom of the amino that is connected in the beta-amino acids that is used to prepare these compounds, and formula Ib compound exhibits is connected on the carbon atom of amino of the beta-amino acids that is used to prepare these compounds and the preferred stereochemistry on two three-dimensional carbon atoms of six hydrogen diaza azepines ketone rings.
As be known in the art, by the suitable modification of method disclosed herein, can obtain synthetic or their chromatography of the independence of these diastereomers and separate.Their the absolute stereo available crystallized product of chemistry or determine with the X-ray crystallography of the reagent deutero-crystallization of intermediate of the asymmetric center that contains known absolute configuration as required.
If desired, separate one enantiomorph thereby the racemic mixture of compound is separable, sepn process can be carried out with methods known in the art, for example with the racemic mixture coupling of compound in enantiopure compound to form non-enantiomer mixture, separate one enantiomorph with standard method subsequently, for example use fractionation crystallization or chromatography.Coupled reaction uses the acid of enantiomer-pure or alkali to form salt usually, and non-enantiomer derivative can be converted into pure enantiomorph by the additional chirality residue that ruptures subsequently.The racemic mixture of compound also can directly utilize chiral stationary phase directly to separate with chromatography, and this method is as known in the art.
Either-or, any enantiomorph of compound can use the reagent of pure raw material of optically-active or configuration known, uses methods known in the art, obtains by stereoselectivity is synthetic.
Should be understood that in this article, mention that compound in structural formula I is meant and also comprise pharmaceutically useful salt, and be not pharmaceutically useful, the salt that uses as free cpds or its pharmaceutically useful salt or the precursor in other synthetic method.
Compound of the present invention can pharmaceutically useful salt form administration, and term " pharmaceutically useful salt " is meant by pharmaceutically useful nontoxic alkali or acid, comprises inorganic or organic bases and salt inorganic or the organic acid preparation.The salt that is included in the basic cpd in the term " pharmaceutically useful salt " is meant the non-toxic salt of The compounds of this invention, and it is usually by making free alkali and suitable organic or inorganic acid-respons preparation.The exemplary salt of basic cpd of the present invention comprises, but be not limited to, as follows: acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, d-camphorsulfonic acid salt, carbonate, muriate, clavulanate, Citrate trianion, dihydrochloride, edetate, ethanedisulphonate, propionic ester dodecyl ester vitriol, esilate, fumarate, the glucoheptose hydrochlorate, gluconate, glutaminate, bismuth glycolyl arsanilate salt, hexylresorcinate, hydrabamine, hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, different thiosulphate, lactic acid salt, Lactobionate, lauroleate, malate, maleate, mandelate, mesylate, MB, methyl nitrate salt, methylsulfuric acid ester salt, mucate, ethyl benzene sulfonate, nitrate, N-methylglucosamine ammonium salt, oleate, oxalate, embonate (embonate), palmitate, pantothenate, phosphate/phosphor acid hydrogen salt, galactosan aldehydic acid salt, salicylate, stearate, vitriol, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.In addition, when The compounds of this invention had acidic-group, its suitable pharmaceutically useful salt included, but not limited to the salt that produced by mineral alkali, comprised aluminium, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, inferior manganese, potassium, sodium, zinc etc.Especially preferred ammonium, calcium, magnesium, potassium and sodium salt.The salt that is produced by pharmaceutically useful organic nontoxic alkali comprises primary, the second month in a season and tertiary amine, cyclammonium, and deacidite, arginine for example, trimethyl-glycine, caffeine, choline, N, the N-dibenzyl-ethylenediamin, diethylamine, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, hydrabamine, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropylamine, the salt of Trometamol etc.
Equally, in compound of the present invention, exist carboxylic acid (COOH) or under the alcohol groups situation, can adopt the pharmaceutically acceptable ester of carboxylic acid derivative, the acyl derivative of methyl, ethyl or valeryl oxygen ylmethyl or alcohol for example, for example, acetic ester or maleic acid ester.Comprise that these esters well known in the prior art and acyl group are to improve solvability or hydrolysis properties to discharge or preceding medicine composition as postponing.
The solvate of compound in structural formula I, especially hydrate comprise in the present invention itself.
Illustrate the present invention and be purposes at embodiment and compound disclosed herein.
Target compound is used for the patient at this process of inhibition of needs, for example suppresses the method for dipeptidyl peptidase-IV enzyme in the Mammals, comprises the compound of effective dosage.The present invention relates to the purposes of compound disclosed herein as the dipeptidyl peptidase-IV activity inhibitor.
Except primates, people for example, various other animals can be treated with method of the present invention, for example, can treat Mammals comprises, but be not limited to ox, sheep, goat, horse, dog, cat, cavy, mouse or other bovid, sheep, horse, dog, feline, rodent or murine.Yet method also can be put into practice in other species, for example birds (for example chicken).
The invention still further relates to preparation and suppress the method for the medicine of dipeptidyl peptidase-IV enzymic activity in human body and animal, it comprises and mixes compound of the present invention and pharmaceutically useful carrier or thinner.
The theme of method treatment of the present invention is Mammals normally, and preferred people is a sex, and it need suppress the dipeptidyl peptidase-IV enzymic activity.Term " treatment significant quantity " is meant that title compound will cause that tissue, system, animal or human's body are by investigator, animal doctor, clinician or the biology of other clinicist approval or the quantity of medicinal response.
The term " composition " that is used for this paper is meant and comprises product, and it contains the concrete composition and the spawn of specific quantity, and it is by directly or indirectly forming with specific quantity mixing special component.This term is used for comprising product when relevant with pharmaceutical composition, inert fraction or spawn that it contains activeconstituents and constitutes carrier, it is by combination, complexing or the gathering of any two or more compositions or by the decomposition of one or more compositions or by the reaction of other type of one or more compositions or interact and directly or indirectly produce.Therefore, pharmaceutical composition of the present invention comprises by mixing any composition of compound of the present invention and pharmaceutically useful preparing carriers." pharmaceutically useful " is meant that carrier, thinner or vehicle must be compatible with other composition of prescription, and be harmless to vehicle.
Term " administration (administration of) " and " administration (administeringa) " compound are interpreted as providing to the individuality of needs treatment the prodrug of compound of the present invention or compound of the present invention.
Compound of the present invention is measured as the method for available this area of application of dipeptidyl peptidase-IV activity inhibitor.It is as follows to suppress constant measuring: connect the fluorescence measurement test and adopt substrate Gly-Pro-AMC, it is ruptured to discharge fluorescence AMC leavings group by DPP-IV.The kinetic parameter of describing this reaction is as follows: K m=50 μ M; k Cat=75s -1k Cat/ K m=1.5 * 10 6M -1s -1In the reaction volume of 1000 μ L altogether, typical reaction contains the 50pM enzyme of having an appointment, and (100mM HEPES, pH 7.5,0.1mg/mlBSA) for 50 μ MGly-Pro-AMC and damping fluid.Being released in the 96 orifice plate photofluorometers of AMC monitored continuously with the excitation wavelength of 360nm and the emission wavelength of 460nm.Under these conditions, in 30 minutes, producing about 0.8 μ M AMC under 25 ℃.Employed enzyme is soluble (diaphragm area is striden in eliminating and the tenuigenin extends) human body protein that produces in baculovirus expression system (Bac-To-Bac, Gibco BRL) in this research.The kinetic constant that is used for hydrolysis Gly-Pro-AMC and GLP-1 is found out according to the literature value that is used for the nature enzyme.For measuring the dissociation constant of compound, the solution of inhibitor in DMSO is added in the reaction that contains enzyme and substrate (final DMSO concentration is 1%), all experiments are at room temperature carried out with above-mentioned standard reaction condition.For measuring dissociation constant (K i), speed of reaction is measured by non-linear decline to the Michaelis-Menton equation that is used to compete inhibition.Error in repeating dissociation constant is usually less than twice.
The compound of following embodiment especially has the activity that suppresses the dipeptidyl peptidase-IV enzyme in above-mentioned test, have the IC that is lower than about 1 μ M usually 50, this result indicates that compound is in the intrinsic activity aspect the dipeptidyl peptidase-IV activity inhibitor.
The dipeptidyl peptidase-IV enzyme is a cell surface proteins, hinting many biological functions, it has tissue distribution (intestines, kidney, liver, pancreas, placenta, thymus gland, spleen, epithelial cell, blood vessel endothelium, lymph and medullary cell, serum) and clearly tissue and cell type expression level widely.DPP-IV is the same with T cell activation mark CD26, at external many immunomodulatorys of rupturing, internal secretion and neuroscience peptide.This has advised the useful effect of this peptase in the various diseases process in people or other species.
Therefore, target compound is used for various preventions or treats the method for following disease, symptom and situation.
Type ii diabetes and related symptoms: people determine that fully incretin GLP-1 and GIP are in vivo by the rapid inactivation of DPP-IV, research and preliminary clinical trial with the DPP-IV deficient mice show that DPP-IV suppresses to have increased the steady-state concentration of GLP-1 and GIP, causes the glucose tolerance of improving.Be similar to GLP-1 and GIP, the peptide that is included in other glucagon family in the glucose adjusting is equally by DPP-IV inactivation (for example PACAP).Work in the DPP-IV inactivation glucose running balance of these peptides.Therefore, DPP-IV inhibitor of the present invention has at the treatment type ii diabetes with in treatment and prevention to be followed usually in type ii diabetes, and comprising in the various symptoms of syndrome X (being also referred to as metabolic syndrome), reaction hypoglycemia and diabetes hyperlipemia has effectiveness.The obesity of following discussion is the another kind of symptom of finding in type ii diabetes, and it can be in response to the treatment of The compounds of this invention.
Following disease, symptom is relevant with type ii diabetes with condition, therefore can treat control or prevention in some cases by compounds for treating of the present invention: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) lipoid dyscrasias, (6) unusual piarhemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL content, (11) high LDL content, (12) atherosclerosis and its sequela, (13) vascular restenosis, (14) Anaphylaxis enteritis, (15) inflammatory enteritis comprises Crohn ' s disease and ulcerative colitis, (16) other inflammatory symptoms, (17) pancreatitis, (18) abdominal obesity, (19) neuroallergy disease, (20) retinopathy, (21) ephrosis, (22) neuropathy, (23) X syndromes, (24) ovarian hyperandrogenism (polycystic ovary syndrome) and other insulin tolerance are the diseases of factor.In syndrome X, be also referred to as metabolic syndrome, obesity is considered to promote insulin tolerance, diabetes, hyperlipemia, hypertension and has increased risk of cardiovascular diseases.Therefore, the DPP-IV inhibitor also can be used for treating the hypertension relevant with these symptoms.
Fat: it is fat that the DPP-IV inhibitor can be used for treatment, and this is based on the inhibition effect that viewed GLP-1 and GLP-2 discharge ingestion of food and stomach.External administration GLP-1 obviously reduces ingestion of food and slows down stomach emptying (Am.J.Physio., 277:R910-R916 (1999)) in human body.The ICV administration of GLP-1 has positive effect (Naturemedicine, 2:1254-1258 (1996)) to ingestion of food equally in rat and mouse.At GLP-1R (-/-)Do not observe the inhibition of feed in the mouse, this represents that these effects transmit by brain GLP-1 acceptor, be similar to GLP-1, GLP-2 is regulated by DPP-IV equally, ICV administration GLP-2 suppresses ingestion of food equally, be similar to the observed effect of GLP-1 (Naturemedicine, 6:802-807 (2000)).In addition, resist the obesity and the related diseases Neo-Confucianism (for example hyperinsulinemia) of diet induced with these animals of research proposal of DPP-IV deficient mice.
Tethelin defective: DPP-IV suppresses to can be used for treating the tethelin defective, and this is based on hypothesis, i.e. somatotropin releasing factor (GRF) a kind ofly stimulates peptide by the prepituitary gland growth hormone releasing in vivo by DPP-IV enzymatic breaking (WO00/56297).Following data are produced evidence, and GRF is an endogenous substance: (1) GRF ruptures to produce inactivation product GRF[3-44 effectively external] (BBA 1122:147-153 (1992)); (2) GRF is lowered into GRF[3-44 rapidly in blood plasma], this is prevented by DPP-IV inhibitor diprotin A; (3) GRF[3-44] discovery (J.Clin.Invest., 83:1533-1540 (1989)) in the blood plasma of human body GRF transgenic pig.Therefore, the DPP-IV inhibitor can be used for being considered to be used for the same range of indication of growth hormone cinogenic agent.
Damage of intestines: the effectiveness of using the operation of DPP-IV inhibitor for treating intestines is by following result of study explanation, glucagon class peptide-2 (GLP-2), the same endogenous substance that is used for DPP-IV, can show nutritive validity (Regulatory Peptides, 90:27-32 (2000)) to intestinal epithelial cells.Administration GLP-2 produces the small intestine quality that increases in rodent, weakens damage of intestines in the rodent model of colitis and enteritis.
Immunosuppression: DPP-IV suppresses to can be used for regulating immune response, and this is based in the T cell activation and increases at chemistry and lives through the research that relates in the journey aspect DPP-IV enzyme and the effectiveness of DPP-IV inhibitor in disease body inner model.DPP-IV has shown and has been same as CD26, a kind of cell surface marker of activating immune cell.The expression of CD26 is regulated by the differentiation of immunocyte and active state, and many chemokinesis factors contain proline(Pro) in penultimate position, infers to be used to protect them in case the degraded of non-special aminopeptidase, and great majority have shown the processing of external DPP-IV.Under some situations (RANTES, LD78-beta, MDC, eotaxin, SDF-lalpha), fracture causes changing in the test of chemotaxis and signal active, also occurs receptor-selective be modified (RANTES) in some cases.Various N-terminal abreviation form of many chemokinesis factors is identified in the cell in vitro culture system, comprises the precognition product of DPP-IV hydrolysis.
The DPP-IV inhibitor has shown that be effective immunosuppressor in transplanting and arthritic animal model.Prodipine (Pro-Pro-phenylbenzene-phosphonic acid ester), the irreversible inhibitor of a kind of DPP-IV shows the survival of double heart allotransplantation in rat, by reached 14 days in 7 days ( Transplantation, 63:1495-1500 (1997)).The DPP-IV inhibitor is research collagen and alkyl diamine inductive sacroiliitis in rat also, in this model, shown the gratifying obvious decay that rear solid end increases [ Lint.J.Immunopharmacology, 19:15-24 (1997) and Immunopharmacology, 40:21-26 (1998)].DPP-IV comprises rheumatic arthritis, multiple sclerosis, Graves disease and Hashimoto thyroiditis (Immunology Today, 20:367-375 (1999)) to the many auto-immune diseases of adjusted.
HIV infects: the DPP-IV restraining effect can be used for treatment or prevention HIV infects or AIDS because the chemokinesis factor that many inhibition HIV cells enter be DPP-IV effective substrate ( Immunology Today20:367-375 (1999)).Under the situation of SDF-1 α, fracture has reduced antiviral activity (PNAS, 95:6331-6 (1998)), therefore will be reduced the HIV infectivity by expection by the stable of the inhibiting SDF-1 α of DPP-IV.
Hemoposieis: DPP-IV suppresses can be used for treatment or prevention blood pressure (hematopiesis), because DPP-IV can be included in the hemoposieis.The DPP-IV inhibitor, Va1-Boro-Pro is in the mouse model moderate stimulation hemoposieis (WO99/56753) of endoxan inductive neutropenia.
Neurone symptom: DPP-IV suppresses to can be used as treatment or prevent various neurones or psychiatric disorders, because many peptides that is included in the various neurone processes are ruptured by DPP-IV external.
Therefore the DPP-IV inhibitor has result of treatment in treatment neurone symptom.
Endomorphin-2, β-casomorphin and Substance P have all shown it is external DPP-IV substrate, and in all cases, external fracture is highly effective, k Cat/ K mBe about 10 6M -1s -1Or it is bigger.Hit in the skip test model at rat analgesia electricity, the DPP-IV inhibitor shows obvious effects, it and the existence of external endomorphin-2 have nothing to do (Brain Research, 815:278-286 (1999)).
The neuroprotective of DPP-IV inhibitor and neurotization effect also protect motor nerve cells in order to avoid the excitotoxin necrocytosis by inhibitor; the striatum innervation of administration MPTP time protection dopaminergic nerve cell and promote the inhibitor ability of the innerv recovery of striatum to confirm in MPTP treatment back during with the therapeutic modality administration at the same time [referring to Yong-Q.Wu etc.; " dipeptidyl peptidase-iv inhibitor neuroprotective effect in vitro and in vivo " (NeuroprotectiveEffects of Inhibitors of Dipeptidyl Peptidase-IV at Vitro and at Vivo) The amino peptidases:Basic of Int.Conf.On Dipeptidyl Science and Clinical Applications, 26-29 day in September, 2002 (Berlin, Germany)].
Cardiovascular disorder: GLP-1 is effectively when being presented at administration after Acute Myocardial Infarction, the mortality ratio (Circulation, 109:962-965 (2004)) that causes improving the left side ventricular function and be reduced in preliminary postangioplasty.The GLP-1 administration also is used for the dog treatment left side ventricle cardiac systolic function obstacle that enlarges the left side ventricular dysfunction that cardiomyopathy and local asphyxia cause suffering from, so susceptible of proof is used for the treatment of patient (US2004/0097411) in heart failure.The DPP-IV inhibitor is expected to show similar effect by the ability of its stable interior GLP-1 of giving birth to.
Tumour infringement and shifting: DPP-IV suppresses can be used for treatment or prophylaxis of tumours infringement and shifts because observed in malignant phenotype's transition process at normal cell the increase expressed in the some exopeptidases that comprising DPP-IV or reduction ( J.Exp.Med., 190:301-305 (1999)).These proteinic adjustings up or down show it is that tissue and cell type are special, and for example the CD26/DPP-IV that increases expresses and observes in thyroid carcinoma, basal cell carcinoma and the mammary cancer of t cell lymphoma, the acute lymphocytoblast leukemia of T cell, origin of cell.Therefore, the DPP-IV inhibitor can be used for treating this cancer.
Benign prostatauxe: the DPP-IV inhibitor can be used for treating benign prostatauxe because by BPH patient in prostata tissue, notice increase the DPP-IV activity ( Eur.J.Clin.Chem.Clin.Biochem., 30:333-338 (1992)).
Sperm motility/male contraception: DPP-IV suppresses to can be used for changing sperm motility and be used for male contraception, this is because in seminal fluid, the cell organelle that the prostatosomes important to sperm motility, prostate gland produce have very high-caliber DPP-IV activity ( Eur.J.Clin.Chem.Clin.Biochem., 30:333-338 (1992)).
Gingivitis: DPP-IV suppresses to can be used for treating gingivitis because in slot liquid and some are mutually related research with tooth root membrane disease severity discovery DPP-IV activity ( Arch.Oral Biol., 37:167-173 (1992)).
Osteoporosis: because gip receptor is present in the sclerocyte, DPP-IV suppresses can be used for treatment or preventing osteoporosis disease.
Compound of the present invention is used for the treatment of or prevents one or more of following symptom or disease: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) lipoid dyscrasias, (6) unusual piarhemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL content, (11) high LDL content, (12) atherosclerosis and its sequela, (13) vascular restenosis, (14) Anaphylaxis enteritis, (15) inflammatory enteritis comprises Crohn ' s disease and ulcerative colitis, (16) other inflammatory symptoms, (17) pancreatitis, (18) abdominal obesity, (19) neuroallergy disease, (20) retinopathy, (21) ephrosis, (22) neuropathy, (23) X syndromes, (24) ovarian hyperandrogenism (polycystic ovary syndrome), (25) type ii diabetes, (26) tethelin defective, (27) neutropenia, (28) neuronal disease, (29) metastases, (30) benign prostatauxe, (32) gingivitis, (33) hypertension, (34) osteoporosis and other symptom that can treat or prevent by the inhibition of DPP-IV.
Motif compound also combines the method that is used to prevent or treat above-mentioned disease, symptom and condition with other medicines.
Compound of the present invention can combine with one or more other medicines and be used for the treatment of, prevents, suppresses or slow down disease or the symptom that formula I compound or other medicines have effectiveness, and it is safer or more effective that its Chinese traditional medicine combines than arbitrary independent medicine.These other medicines can be by approach and quantity and formula I compound while or the administration of adopting usually successively.When formula I compound and one or more other medicines use simultaneously, preferably contain the pharmaceutical composition in unit dose form of these other medicines and formula I compound.Yet combined treatment also can comprise treatment, and its Chinese style I compound and one or more other medicines are to show administration different overlapping time.Also expect when being used in combination using when compound of the present invention and other activeconstituents can use than difference is independent than low dosage with one or more other activeconstituentss.Therefore, pharmaceutical composition of the present invention comprises contain one or more other composition of active components except that formula I compound.
Can combine administration with formula I compound, or other activeconstituents individually dosed or in same pharmaceutical composition includes, but are not limited to:
(a) other DPP IV (DPP-IV) inhibitor;
(b) insulin sensitivity medicine, comprise (i) PPAR gamma agonist, for example glitazone (for example troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone etc.) and other PPAR part, comprise the PPAR alpha/gamma double agonists, for example KRP-297 and PPAR alfa agonists, Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate) for example, (ii) biguanides, for example metformin and phenformin and (iii) protein-tyrosine phosphonic acids enzyme-1B (PTP-1B) inhibitor;
(c) Regular Insulin and insulin-mimickers;
(d) sulfonylurea and other insulin secretagogue, for example tolbutamide, Glipizide, glimepiride and meglitinide and related substances, for example repaglinide;
(e) alpha-glucosidase inhibitor (for example acarbose);
(f) glucagon receptor antagonist, for example disclosed material in WO 98/04528, WO99/01423, WO00/39088 and WO00/69810;
(g) GLP-1, GLP-1 analogue and GLP-1 receptor stimulant, for example disclosed material in WO00/42026 and WO00/59887;
(h) GIP, GIP stand-in, for example disclosed material and gip receptor agonist in WO00/58360;
(i) PACAP, PACAP stand-in and PACAP receptor stimulant are for example at the disclosed material of WO01/23420;
(j) cholesterol reduces medicine, (i) HMG-CoA reductase inhibitor (lovastatin for example, Simvastatin, Pravastatin, Cerivastatin, fluvastatin, atorvastatin, cut down his spit of fland of Ta Ting and Lou rosuvastatin and other according to it), (ii) sequestrant (QUESTRAN, the dialkyl aminoalkyl derivative that colestipol and crosslinked Portugal are poly-), (iii) nicotine alcohol, niacin or its salt, (iv) PPAR alfa agonists, Fenofibric Acid derivative (gemfibrozil for example, clofibrate, fenofibrate and bezafibrate), (v) PPAR alpha/gamma double agonists, KRP-297 for example, (vi) cholesterol absorption inhibitor, for example β-Gu Zaichun and ezetimibe, (vii) acyl-CoA: chole-sterol acyltransferase inhibitor, for example avasimibe and (viii) antioxidant, for example probucol;
(k) PPAR delta agonists, for example disclosed material in WO97/28149;
(1) anti-obesity compound, for example Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide tyrosine 1Or Y 5Antagonist, CB1 receptor inverse agonists and antagonist, β 3Adrenoceptor agonists, black adrenal cortical hormone receptor agonist, especially black adrenocortical hormone-4 receptor stimulant, ghrelin antagonist and melanin concentration hormone (MCH) receptor antagonist;
(m) ileal bile acid transfer inhibitor;
(n) be used for the medicine of inflammation, for example Asprin, non-steroidal anti-inflammatory drug, azulfidine, azulfidine and selectivity epoxy enzyme-2 inhibitor;
(o) antihypertensive drug, for example ACE inhibitor (enalapril, lisinopril, captopril, quinapril, tandolapril), A-II receptor blocking agent (losartan, Candesartan, irbesartan, valsartan, telmisartan, Eprosartan), Beta receptor blockers and calcium channel blocker; With
(p) glucokinase activators (GKA), for example disclosed material in WO03/015774;
(q) 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor, for example at US6, disclosed material in 730,690; With
(r) cholesteryl transesterify protein (CETP) inhibitor, for example torcetrapib.
Can be included in WO03/004498 (16.01.2003) with structural formula I compound bonded dipeptidyl peptidase-iv inhibitor, WO03/004496 (16.01.2003), EP1258 476 (20.11.2002), WO 02/083128 (24.10.2002), WO02/062764 (15.08.2002), WO03/000250 (3.01.2003), WO03/002530 (9.01.2003), WO03/002531 (9.01.2003), WO03/002553 (9.01.2003), WO03/002593 (9.01.2003), WO03/000180 (3.01.2003) and WO03/000181 (3.01.2003).Specific DPP-IV inhibitor compound comprises Isoleucine thiazolidide (P32/98), NVP-DPP-728, LAF 237, P93/01 and BMS 477118.
Can comprise Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide tyrosine with compound in structural formula I bonded anti-obesity compound 1Or Y 5Antagonist, cannabinoid CB 1 receptor antagonist or inverse agonist, black adrenal cortical hormone receptor agonist, especially black adrenocortical hormone-4 receptor stimulant, ghrelin antagonist and melanin concentration hormone (MCH) receptor antagonist.As to can with the review of structural formula I compound bonded anti-obesity compound, referring to S.Chaki etc., " Recent advances is at feeding suppressingagents:potential therapeutic strategy for the treatment ofobesity " Expert Opin.Ther.Patents, 11:1677-1692 (2001) and D.Spanswick and K.Lee, " Emerging antiobesitydrugs, " Expert Opin.Emerging Drugs, 8:217-237 (2003).
Can be included in U.S.6 with structural formula I compound bonded neuropeptide Y 5 antagonist, 335, disclosed material among 345 (1.01.2002) and the WO 01/14376 (1.03.2001), specific compound is defined as GW 59884A, GW569180A, LY366377 and CGP-71683A.
Can be included in the open WO 03/007887 of PCT with structural formula compound bonded cannabinoid CB 1 receptor antagonist; U.S.5,624,941, for example rimonabant, PCT disclose WO02/076949, for example SLV-319, U.S.6,028,084, open WO 00/10968, PCT of PCT open WO 98/41519, PCT open WO 99/02499, U.S.5,532, disclosed material in 237 and U.S5,292,736.
Can be included in WO03/009847 (6.02.2003) with the black adrenal cortical hormone receptor agonist of formula I compound bonded; WO 02/068388 (6.09.2002); WO99/64002 (16.12.1999); WO00/74679 (14.12.2000); WO01/70708 (27.09.2001); And disclosed material and at J.D.Speake etc., " Recent advances is at the develop-mentofmelanocortin-4 receptoragonists, " among the WO01/70337 (27.09.2001) Expert Opin.Ther.Patents, disclosed material among the 12:1631-1638 (2002).
Be used for the treatment of the safety of diabetes and effectively glucokinase (GKA) activator effectively be applied in J.Grimsby etc., " Allosteric Activators of Glucokinase:Potential Role is at Diabetes Therapy, " Science, discuss among the 301:370-373 (2003).
When compound of the present invention and one or more other medicines use simultaneously, preferably except that compound of the present invention, contain the pharmaceutical composition of these other medicines.Therefore, pharmaceutical composition of the present invention comprises composition, and it also contains one or more other activeconstituentss except that compound of the present invention.
The weight ratio of compound of the present invention and second kind of activeconstituents can change, and will depend on the effective dose of every kind of composition, will use every kind effective dose usually.Therefore, for example when compound of the present invention combines with another kind of medicine, the weight ratio of compound of the present invention and other medicines will be about 1000 usually: about 1: 1000 of 1-, preferred about 200: about 1: 200 of 1-.Compound of the present invention and other activeconstituents combine will be usually also in above-mentioned scope, but in each case, should use the effective dose of every kind of activeconstituents.
In this combination, compound of the present invention and other activeconstituents can be individually or administration jointly.In addition, a kind of administration of composition can be before the other medicines administration, simultaneously or afterwards.
Compound of the present invention can be oral usually, parenteral (for example intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or transfusion, subcutaneous injection or transfusion), suck in spraying, the nose, in the sheath, internal rectum, hypogloeeis or topical routes, can be separately or together to contain the appropriate units dosage preparation of the nontoxic pharmaceutically useful carrier, auxiliary material and the vehicle that are applicable to every kind of route of administration.Remove the treatment warm-blooded animal, for example outside mouse, rat, horse, ox, sheep, dog, cat, the monkey etc., compound of the present invention is effective to human body.
The pharmaceutical composition that is used for administration compound of the present invention can exist with unit dosage form easily, can be by any currently known methods preparation of pharmacy field.All methods comprise makes activeconstituents and the carrier blended step that constitutes one or more supplementary components.Usually pharmaceutical composition can subsequently if desired, be configured as required preparation with product by making the broken solid carrier of liquid vehicle or fine powder or both all even close mixing.In pharmaceutical composition, comprised the active motif compound that is enough to lysis or symptom are produced the quantity of required effect.The term " composition " that is used for this paper comprises product, and it contains the special component of specific quantity, and mixes the spawn that directly or indirectly produces by the special component of specific quantity.
The pharmaceutical composition that contains activeconstituents can be to be applicable to the form that orally uses, but for example tablet, tablet, lozenge, moisture or oil suspension dispersed powders or particle, emulsion, hard or soft capsule or syrup or elixir.The composition that is used to orally use can be used to produce any currently known methods preparation of pharmaceutical composition according to this area, and said composition can contain one or more reagent that are selected from sweetener, seasonings, tinting material and sanitas to provide pharmacopedics graceful and delicious preparation.Tablet contains and the activeconstituents that is applicable to the nontoxic pharmaceutically useful mixed with excipients of producing tablet, and these vehicle for example can be, inert support, for example lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example starch, gelatin or Sudan Gum-arabic and lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can be uncoated or with known technology coated with delay disintegration or the absorption in gi tract, thereby the effect of delay in a long time is provided, for example can adopt the time lag material, for example glycerol monostearate or glyceryl stearate.They also can be used on US4, and the technology of describing in 256,108,4,166,452 and 4,265,874 is coated with the osmotic therapeutic tablets that is formed for sustained release.
The preparation that is used to orally use can also exist as hard gelatin capsule, wherein activeconstituents and inert solid diluent, for example lime carbonate, calcium phosphate or kaolin mix, or exist as soft gelatin capsule, wherein activeconstituents and water or oily medium, for example peanut oil, whiteruss or the oil mixing of olive hurdle.
Aq suspension contains and the activeconstituents that is applicable to the mixed with excipients of producing aq suspension, this vehicle is a suspension agent, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, Polyvinylpyrolidone (PVP), tragacanth and Sudan Gum-arabic; Dispersion or moistening agent can be the phosphatide of natural generation, the condensation product of Yelkin TTS or alkylene oxide and lipid acid for example, the condensation product of polyoxyethylene stearic acid ester or oxyethane and long chain aliphatic for example, heptadecyl vinyloxy group hexadecanol for example, or the condensation product of oxyethane and the part ester that obtains by lipid acid and hexitol, the for example condensation product of the part ester that obtains of polyoxyethylene sorbitol monoleate or oxyethane and lipid acid and hexitan, for example polyethylene dehydrated sorbitol mono-fatty acid ester.Aq suspension also can contain one or more sanitass, for example P-hydroxybenzoic acid ethyl or n-propyl ester, one or more tinting materials, one or more seasoningss and one or more sweeteners, for example sucrose or asccharin.
Containing oil suspension can be by being suspended in vegetables oil with activeconstituents, and for example Peanut oil, olive hurdle oil, sesame oil or Oleum Cocois or at mineral oil are for example prepared in the whiteruss.Contain oil suspension and can contain thickening material, for example beeswax, paraffinum durum or hexadecanol can add sweetener, and for example aforesaid those and seasonings are to provide delicious oral preparations, and these compositions can be by adding antioxidant, and for example xitix is anticorrosion.
But being applicable to by adding dispersed powders and the particle that entry prepares aq suspension provides and dispersion agent or moistening agent, suspension agent and one or more sanitas blended activeconstituentss.Suitable dispersion agent or moistening agent and suspension agent mention by above-mentioned those for example, can have additional vehicle, for example increase sweet, seasoning and tinting material.
Pharmaceutical composition of the present invention can also be the O/w emulsion form, and oil phase can be a vegetables oil, for example olive hurdle oil or Peanut oil or mineral oil, for example whiteruss or their mixture.Suitable emulsifying agent can be the resin of natural generation, for example the phosphatide soybean of Sudan Gum-arabic or tragacanth gum, natural generation, Yelkin TTS and the ester or the part ester that produce by lipid acid and hexitan, the for example condensation product of dehydrated sorbitol mono-fatty acid ester and described part ester and oxyethane, for example polyoxyethylene sorbitan monoleate.Emulsion also can contain and increases sweet and seasonings.
Syrup and elixir can be used sweetener, for example glycerine, propylene glycol, Sorbitol Powder or sucrose preparation, and said preparation also can contain negative catalyst, sanitas and seasoning and tinting material.
Pharmaceutical composition can be that sterile injectable is moisture or contain oil suspension, and this suspension can be according to known technology with aforesaid those suitable dispersions or moistening agent and suspension agent preparation.Sterile injectable preparation can also be at nontoxic parenteral acceptable diluent or solvent, for example sterile injectable solution or the suspension in the solution in 1,3 butylene glycol.In pharmaceutically useful vehicle and solvent, can adopt water, Ringer solution and isotonic sodium chlorrde solution.In addition, aseptic expressed oil purposes solvent or suspension medium easily.For this reason, can use any mixing expressed oil, comprise synthetic single or two glyceryl ester.In addition, lipid acid, for example oleic acid can be used in the injectable preparation.
Compound of the present invention can also be used for the suppository form administration of rectum drug administration, these compositions can by hybrid medicine and suitable be solid at normal temperatures, but under rectal temperature the non-stimulation mixed with excipients preparation of liquid, therefore be melted in the rectum to discharge medicine, this material is theobroma oil and polyoxyethylene glycol.
Be used for local the use, adopt emulsion, ointment, gelifying agent, solution or the suspension etc. that contain compound of the present invention.(purposes for this reason, topical application will comprise collutory and gargle.)
Pharmaceutical composition of the present invention and method also can contain other other therapeutical active compound of as above mentioning, and they are applied to the above-mentioned pathology symptom of treatment usually.
Need to suppress in the symptom of dipeptidyl peptidase-IV enzymic activity in treatment or prevention, normally suitable dosage level will be every approximately kg weight in patients 0.01-500mg every day, and it can the single or multiple administration.Preferred dosage level will be the about 250mg/kg of about 0.1-every day, more preferably the about 100mg/kg of about 0.5-every day.The proper dosage level can be about 0.01-250mg/kg every day, every day about 0.05-100mg/kg, or every day about 0.1-50mg/kg.In this scope, dosage can be every day 0.05-0.5,0.5-5 or 5-50mg/kg.For oral administration, composition preferably provides with the tablet form that contains the 1.0-1000mg activeconstituents, and the symptom that is used for the patient that treated is regulated dosage especially 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0mg.Compound can be with 1-4 time system administration every day, preferably once a day or twice.
When the disease of treatment or prevent diabetes and/or hypertension or hypertriglyceridemia or other compound indication of the present invention, when compound of the present invention with every kilogram of about 100mg of the about 0.1mg-of the weight of animals, preferably, obtain gratifying result usually as single per daily dose or the dosage one day 2-6 time that separates or when postponing the releasing pattern administration.To most of large mammals, total per daily dose is the about 1000mg of about 1.0mg-, the about 50mg of preferably about 1mg-.Under 70kg adult's situation, total per daily dose will be the about 350mg of about 7mg-usually, and this dosage regimen can be regulated so that the optimal treatment response to be provided.
Yet, should understand and to change concrete dosage level of any particular patient and dose frequency, various factors be will depend on, the activity of the particular compound that is adopted, metabolic stability and action length, age, body weight, general health situation, sex, diet, administering mode and time, secreting rate, drug regimen, the severity of specific symptoms and the treatment of host's experience of compound comprised.
Following scheme and embodiment illustrate the whole bag of tricks of preparation The compounds of this invention, and raw material illustrates preparation according to methods known in the art or as this paper.
Compound of the present invention can be by the beta-amino acids intermediate; six hydrogen diaza azepines intermediates of the material of formula II and replacement for example; for example the material of formula III uses the deprotection preparation subsequently of standard peptide coupling condition, and the preparation of these intermediates is described in following scheme.
Wherein Ar, R 1, R 4, R 5, R 6, R 7, R 8, R 9, R 10And R 11Be as defined above, P is suitable nitrogen-protecting group group, for example tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) or 9-fluorenyl methoxy carbonyl (Fmoc).
Scheme 1
Formula II compound is commercial acquisition, knownly in the document maybe can prepare easily by the method that various those skilled in the art are familiar with, and a kind of conventional route is in scheme 1 illustrated.It can be a-amino acid commercial acquisition or that easily pass through to protect the protection of preparation with for example di-t-butyl pyrocarbonate (P=BOC), carbonyl benzyloxy chlorine (P=Cbz) or N-(9-fluorenyl methoxy ketonic oxygen base) succinimide (P=Fmoc) by corresponding amino acid 1With isobutyl chloroformate and alkali, for example triethylamine or diisopropylethylamine are handled with diazomethane subsequently.The diazo ketone that obtains uses silver benzoate at solvent subsequently, for example handles in methyl alcohol or the moisture two  alkane, can be according to Sewald etc., and Synthesis, 837 (1997) method is carried out supersound process to obtain beta amino acids II.It will be apparent to one skilled in the art that beta amino acids II, can use the alpha amino acid I of enantiomer-pure for the preparation enantiomer-pure.The another kind of approach of protection beta-amino acids intermediate II can find in following comment: E.Juaristi, Enantioselective Synthesis of Beta-amino Acids.Ed., Wiley-VCH, New York:1997; Juaristi etc., Aldrichimica Acta, 27:3 (1994); With Cole etc., Tetrahedron, 32:9517 (1994).
Scheme 2
Figure A20048002218400421
The formula III compound is commercial the acquisition, and document is known maybe can be prepared easily by the method that various those skilled in the art are familiar with.A kind of method easily is in scheme 2Middle demonstration, amino ester 2 usefulness trimethyl aluminium cyclisation are six hydrogen diaza azepines of N-protected 3, deprotection, for example sour by using under the situation of Boc, for example hydrochloric acid in two  alkane or the trifluoroacetic acid in methylene dichloride are handled and are obtained intermediate III.
Scheme 3
Amino ester 2Be knownly in the document maybe can to prepare easily by the whole bag of tricks that those skilled in the art are familiar with.R wherein 1, R 6, R 7And R 9Be that H and P are that a kind of facilitated method of Boc group is shown in scheme 3.Amino ester 4 is used as its hydrochloride, easily with vinyl cyanide 5Condensation, the amino of the product of formation is by for example protection obtains as its tert-butoxycarbonyl (Boc) derivative 6Cyano reduction for example by using hydrogen treat, uses platinum-oxide catalyst, obtains amine 2a
Scheme 4
Figure A20048002218400431
Be used to prepare wherein R 10And R 11Be the amine of H 2Another kind of method as shown in scheme 4.Amino acid 7With N, the O-dimethylamine uses coupling reagent easily, and for example EDC/HOBt coupling obtains aldehyde with the Weinreb reduction of amide that obtains 8Aldehyde is handled with amino ester, and corresponding imines reduces under use catalytic hydrogenation condition.The secondary amine that obtains is for example protected to obtain ester as its Cbz derivative subsequently 10(P=Cbz).The deprotection of terminal amino group obtains required intermediate 2b
Scheme 5
Figure A20048002218400441
Prepare wherein R 5, R 10And R 11The another kind of method of six hydrogen diaza azepines that is H is as shown in scheme 5.α-ketone group acid 11, for example pyruvic acid can with aminopropionitrile 12Condensation is to obtain cyano ethyl oxygen base propionic acid amide 13, its available reductive agent, for example platinum oxide and hydrogen reducing cyclisation are to obtain six hydrogen diaza azepines III.
Scheme 6
Six hydrogen diaza azepines III and be used for its synthetic intermediate modification in every way, for example, as shown in scheme 6, as the wherein R of preparation as described in the intermediate 3 (scheme 2) 1It is the intermediate of H 14Amide nitrogen can be by using alkali, for example the sodium hydride deprotection is handled alkylation with alkylogen subsequently, the intermediate deprotection that obtains obtains intermediate III.
Scheme 7
Another kind of such given an example as scheme 7 illustrated.In scheme 6 as intermediate 15Described preparation or the wherein R for preparing by the protection intermediate III 4And/or R 5Be six hydrogen diaza azepines of the protection of H 16Can be by using highly basic, for example the LDA deprotection is handled alkylation with alkylogen subsequently, and this method can be repeated to introduces second alkyl R 5, deprotection obtains intermediate III.
Scheme 8
Figure A20048002218400461
As shown in scheme 8, intermediate II and III are under standard peptide coupling condition, for example use at solvent, N for example, 1-ethyl-3-in dinethylformamide (DMF) or the methylene dichloride (3-dimethylaminopropyl) carbodiimide and I-hydroxybenzotriazole (EDC/HOBT) or O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate and 1-hydroxyl-7-azepine benzotriazole (HATU/HOAT) obtained intermediate 17 at room temperature coupling 3-48 hour.In some cases, intermediate III can be a salt, and for example hydrochloride or trifluoroacetate in these cases, are to add alkali in coupled reaction easily, N normally, N-diisopropylethylamine.Under the situation of Boc, blocking group is usefulness subsequently, and for example trifluoroacetic acid or formate hydrochlorate are removed and obtained required amine I.If desired, product is for example used Biotage  device or HPLC purifying by recrystallization, development, preparative thin layer chromatography, fast silica gel chromatogram method.Compound with the HPLC purifying is separable into corresponding salt, and the purifying of intermediate is realized in the same manner.
In some cases, in the product I or the further modification of synthetic intermediate of such scheme illustrated, for example handle at Ar, R 1, R 4, R 5, R 6, R 7, R 8, R 9, R 10And R 11On substituting group.These processing can include, but not limited to reduction, oxidation, alkylation, acylations and hydrolysis reaction, and these are that those skilled in the art are familiar with.
In some cases, the order of carrying out above-mentioned reaction scheme can change to help reaction or to avoid undesired reaction product.Provide following embodiment to more fully understand invention, these embodiment only are used to illustrate, and should not constitute the restriction to inventing by any way.
Intermediate 1
(3R)-and the 3-[(tert-butoxycarbonyl) amino]-4-(2, the 5-difluorophenyl) butyric acid
Steps A: (R, S)-N-(tert-butoxycarbonyl)-2,5-difluorophenyl Beta Alanine
To 0.5g (2.49mmol) 2, add 2N aqueous naoh solution and the 543mg di-t-butyl pyrocarbonate of 1.5mL in the solution of 5-two fluoro-DL-phenylpropylamine acid in the 5mL trimethyl carbinol successively, reaction was at room temperature stirred 16 hours, diluted with ethyl acetate.Organic phase is used 1N hydrochloric acid and aqueous salt solution successively, uses dried over mgso, vacuum concentration.(silica gel, 97: 2: 1 methylene dichloride: methyl alcohol: acetate) purifying obtains title compound to thick material with flash chromatography.LC/MS302(M+1)。
Step B:(R, S)-the 3-[(tert-butoxycarbonyl) amino]-1-diaza-4-(25-two fluoro-phenyl) fourth-2-ketone
At 0 ℃ to 2.23g (7.4mmol) (R, S)-N-(tert-butoxycarbonyl)-2, add 1.37mL (8.1mmol) triethylamine and 0.931mL (7.5mmol) tertiary butyl chloride manthanoate in the solution of 5 difluorophenyl Beta Alanines in the 100mL ether successively, be reflected at this temperature and stirred 15 minutes.The cooling ethereal solution that adds diazomethane subsequently continues until yellow, continues to stir 16 hours again.Extinguish excessive diazomethane by dripping acetate, reaction is used 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and salt water washing successively with the ethyl acetate dilution, with dried over mgso and vacuum concentration.(silica gel, 4: 1 hexanes: ethyl acetate) purifying obtains title compound diazo ketone with flash chromatography.
1H NMR(500MHz，CDCl 3)δ7.03-6.95(m，1H)，6.95-6.88(m，2H)，5.43(bs，1H)，5.18(bs，1H)，4.45(bs，1H)，3.19-3.12(m，1H)，2.97-2.80(m，1H)，1.38(s，9H)。
Step C:(3R)-and the 3-[(tert-butoxycarbonyl) amino]-4-(2, the 5-difluorophenyl) butyric acid
At-30 ℃ to 2.14g (6.58mmol) (R, S)-the 3-[(tert-butoxycarbonyl)-amino]-1-diazo-4-(2, the 5-difluorophenyl) fourth-2-ketone is dissolved in the 3.3mL of adding successively (19mmol) N in the 100mL methyl alcohol, N-diisopropylethylamine and 302mg (1.32mmol) silver benzoate.Reaction was stirred 90 minutes, with the ethyl acetate dilution, used 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and salt water washing successively subsequently.The organic phase dried over mgso, vacuum concentration, enantiomorph obtains at first required (the R)-enantiomorph of wash-out of 550mg with preparation property chirality HPLC (Chiralpak AD post, 5% ethanol in hexane) separation.With substance dissolves at the 50mL tetrahydrofuran (THF): methyl alcohol: in the mixture of 1N aqueous lithium hydroxide (3: 1: 1), stirred 4 hours at 50 ℃.To react cooling,, use ethyl acetate extraction with 5% dilute hydrochloric acid acidifying.The organic phase aqueous salt solution washing that merges obtains the title compound white solid foam with dried over mgso and vacuum concentration.
1H NMR(500MHz，CDCl 3)δ7.21(m，1H)，6.98(m，2H)，6.10(bs，1H)，5.05(m，1H)，4.21(m，1H)，2.98(m，2H)，2.60(m，2H)，1.38(s，9H)。
Intermediate 2
Figure A20048002218400481
(3R)-and the 3-[(tert-butoxycarbonyl) amino]-4-[2-fluoro-4-(trifluoromethyl) phenyl]-butyric acid
Steps A: (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-(2 '-fluoro-4 '-(trifluoromethyl) benzyl)-5-isopropylpyrazine
-70 ℃ of (2S)-2 to the commercial acquisition of 3.32g (18mmol), 5-dihydro-3 adds the 1.6M solution of 12mL (19mmol) butyllithium in hexane in the 6-dimethoxy-solution of 2-isopropylpyrazine in the 100mL tetrahydrofuran (THF).After stirring 20 minutes under this temperature, be added in 5g (19.5mmol) the 2-fluoro-4-trifluoromethyl benzyl bromine in the 20mL tetrahydrofuran (THF), continue to stir warm subsequently the reaction 3 hours to room temperature.The reaction water stops, and vacuum concentration is used ethyl acetate extraction.The organic phase salt water washing that merges, drying and vacuum concentration obtain title compound with flash chromatography (silica gel, the 0-5% ethyl acetate in hexane) purifying.
1H NMR(500MHz，CDCl 3)δ7.33-7.25(m，3H)，4.35-4.31(m，1H)，3.75(s，3H)，3.65(s，3H)，3.60(t，1H，J＝3.4Hz)，3.33(dd，1H，J＝4.6，13.5Hz)，3.03(dd，1H，J＝7，13.5Hz)，2.25-2.15(m，1H)，1.0(d，3H，J＝7Hz)，0.66(d，3H，J＝7Hz)。
Step B:(R)-N-(tert-butoxycarbonyl)-2-fluoro-4-trifluoromethyl-phenylpropylamine acid methyl esters
To 5.5g (15mmol) (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-(2 '-fluoro-4 '-(trifluoromethyl) benzyl)-5-isopropylpyrazine are at the 50mL acetonitrile: the moisture trifluoroacetic acid of 1N that adds 80mL in the solution in the mixture of methylene dichloride (10: 1).Reaction was stirred 6 hours, and vacuum is removed organic solvent, and adding sodium sulfate is alkalescence (pH is greater than 8) until solution, with the dilution of 100mL tetrahydrofuran (THF), added 10g (46mmol) di-t-butyl pyrocarbonate with afterreaction.The slurry that obtains stirred 16 hours, and vacuum concentration is used ethyl acetate extraction.The organic phase salt water washing that merges, drying and vacuum concentration.Obtain title compound with flash chromatography (silica gel, 20% ethyl acetate in hexane) purifying.
1H NMR(500MHz，CDCl 3)δ7.38-7.28(m，3H)，5.10(bd，1H)，4.65-3.98(m，1H)，3.76(s，3H)，3.32-3.25(m，1H)，3.13-3.05(m，1H)，1.40(s，9H)。
Step C:(R)-and N-(tert-butoxycarbonyl)-2-fluoro-4-trifluoromethyl) phenyl-Beta Alanine
With 5.1g (14mmol) (R, S)-N-(tert-butoxycarbonyl)-2-fluoro-4-trifluoromethyl) phenylpropylamine acid methyl esters at the 350mL tetrahydrofuran (THF): methyl alcohol: the solution in the mixture of 1N lithium hydroxide (3: 1: 1) stirred 4 hours at 50 ℃.To react cooling, use 5% hcl acidifying, use ethyl acetate extraction.Dried over mgso is used in the organic phase salt water washing that merges, and vacuum concentration obtains title compound.
1H NMR(500MHz，CD 3OD)δ7.45-7.38(m，3H)，4.44-4.40(m，1H)，3.38-3.33(m，1H)，2.98(dd，1H，J＝9.6，13.5Hz)，1.44(s，9H)。
Step D:(3R)-and the 3-[(tert-butoxycarbonyl) amino]-4-] 2-fluoro-4-(trifluoromethyl)-phenyl] butyric acid
In the solution of 3.4g (9.7mmol) step C product in the 60mL tetrahydrofuran (THF), add 2.3mL (13mmol) diisopropylethylamine and 1.7mL (13mmol) isobutyl chloroformate successively at 0 ℃, be reflected at this temperature and stirred 30 minutes.The cooling ethereal solution that adds diazomethane subsequently continues until yellow, continues to stir 16 hours again.Extinguish excessive diazomethane by dripping acetate, reaction is used 5% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and salt water washing successively with the ethyl acetate dilution, with dried over mgso and vacuum concentration.(silica gel, 9: 1 hexanes: ethyl acetate) purifying obtains 0.5g diazo ketone with flash chromatography.In being dissolved in solution in the 100mL methyl alcohol, 0.5g (1.33mmol) diazo ketone adds 0.7mL (4mmol) diisopropylethylamine and 32mg (0.13mmol) silver benzoate at 0 ℃ successively.Reaction was stirred 2 hours, with the ethyl acetate dilution, used 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and salt water washing successively subsequently.The organic phase dried over mgso, vacuum concentration is dissolved in the 50mL tetrahydrofuran (THF): methyl alcohol: in the mixture of 1N aqueous lithium hydroxide (3: 1: 1), stirred 3 hours at 50 ℃.To react cooling,, use ethyl acetate extraction with 5% dilute hydrochloric acid acidifying.The organic phase salt water washing that merges obtains the title compound white solid foam with dried over mgso and vacuum concentration.
1H NMR(500MHz，CD 3OD)：δ7.47-7.33(m，3H)，4.88(bs，1H)，4.26-3.98(m，1H)，3.06-3.01(m，1H)，2.83-2.77(m，1H)，2.58-2.50(m，2H)，1.29(s，9H)。
Intermediate 3
(3R)-and the 3-[(tert-butoxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid
Steps A: (2S, 5R)-2,5-dihydro-3,6-dimethoxy-2-sec.-propyl-5-(2 ', 4 ', 5 '-trifluoro-benzyl)-pyrazine
With the described method of intermediate 2 steps A (2S)-2 by 3.42g (18.5mmol), 5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and 5g (22.3mmol) 2,4,5-trifluoro-benzyl bromine prepares title compound (3.81g).
1H NMR(500MHz，CDCl 3)：δ7.01(m，1H)，6.85(m，1H)，4.22(m，1H)，3.78(m，3H)，3.64(m，3H)，3.61(m，1H)，3.20(m，1H)，2.98(m，1H)，2.20(m，1H)，0.99(d，3H，J＝8Hz)，0.62(d，3H，J＝8Hz)。
Step B:(R)-and N-(tert-butoxycarbonyl)-2,4,5-trifluorophenyl alanine methyl ester
(2S, 5R)-2,5-dihydro-3 adds the 2N hydrochloric acid of 20mL in the solution of 6-dimethoxy-2-sec.-propyl-5-(2 ', 4 ', 5 '-trifluoro-benzyl) pyrazine in the 20mL acetonitrile to 3.81g (11.6mmol).Reaction was stirred 72 hours, vacuum concentration.Resistates is dissolved in the 30mL methylene dichloride, adds 10mL (72mmol) and 9.68g (44.8mmol) di-t-butyl pyrocarbonate.Reaction was stirred 16 hours, with the ethyl acetate dilution, used 1N hydrochloric acid and salt water washing successively.The organic phase dried over sodium sulfate, vacuum concentration, (silica gel, 9: 1 hexanes: ethyl acetate) purifying obtains title compound with flash chromatography.
1H NMR(500MHz，CDCl 3)：δ6.99(m，1H)，6.94(m，1H)，5.08(m，1H)，4.58(m，1H)，3.78(m，3H)，3.19(m，1H)，3.01(m，1H)，1.41(s，9H)。
Step C:(R)-and N-(tert-butoxycarbonyl)-2,4,5-trifluorophenyl Beta Alanine
With the described method of intermediate 2 step C by 2.41g (7.5mmol) (R)-N-(tert-butoxycarbonyl)-2,4,5-trifluorophenyl Beta Alanine methyl esters prepares title compound (2.01g).
LC/MS 220.9(M+1-BOC)。
Step D:(3R)-and the 3-[(tert-butoxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl)-butyric acid
-20 ℃ to 0.37g (1.16mmol) (R)-N-(1,1-dimethyl methoxy base carbonyl)-2,4, add 0.193mL (1.3mmol) triethylamine and 0.18mL (1.3mmol) isobutyl chloroformate in the solution of 5-trifluorophenyl Beta Alanine in the 10mL ether successively, be reflected at this temperature and stirred 15 minutes.The cooling ethereal solution that adds diazomethane subsequently continues until yellow, continues to stir 1 hour again.Extinguish excessive diazomethane by dripping acetate, reaction is used saturated aqueous sodium hydrogen carbonate solution and salt water washing successively with the ethyl acetate dilution, with dried over mgso and vacuum concentration.(silica gel, 3: 1 hexanes: ethyl acetate) purifying obtains 0.36g diazo ketone with flash chromatography.Be dissolved in 1 of 12mL to 0.35g (1.15mmol) diazo ketone, 4-two  alkane: add 26mg (0.113mmol) silver benzoate in the solution in the water (5: 1).Reaction was stirred 2 hours, with the ethyl acetate dilution, used 1N hydrochloric acid and salt water washing successively subsequently, used dried over mgso, vacuum concentration.(silica gel, 97: 2: 1 methylene dichloride: methyl alcohol: acetate) purifying obtains title compound with flash chromatography.
1H NMR(500MHz，CDCl 3)：δ7.06(m，1H)，6.95(m，1H)，5.06(bs，1H)，4.18(m，1H)，2.98(m，2H)，2.61(m，2H)，1.39(s，9H)。
Intermediate 4
(3R)-and 4-(2-bromo-4,5-difluorophenyl)-3-[(tert-butoxycarbonyl) amino]-butyric acid
To 2.4g (10mmol) 2-bromo-4, the 5-difluoro-benzoic acid [according to Braish etc., Syn. Comm., the preparation of the method for 3067-3074 (1992)] add 2.43g (15mmol) carbonyl bisglyoxaline in the solution in the 75mL tetrahydrofuran (THF), behind the solution reflux 3.5h, cool to room temperature is added in 0.38g (10mmol) sodium borohydride in the 15mL water.Reaction was stirred 10 minutes, distributed between ethyl acetate and 10% aqueous carbonic acid hydrogen sodium solution.Organic layer is with warm water and salt solution washed twice, with dried over mgso and vacuum concentration.(silica gel, 4: 1 hexanes: ethyl acetate) purifying obtains 1.9g 2-bromo-4,5-difluorobenzyl alcohol with flash chromatography.At 0 ℃ to 1.9g (8.4mmol) 2-bromo-4, add 3.4g (10mmol) carbon tetrabromide and 2.7g (10mmol) triphenylphosphine in the solution of 5-difluorobenzyl alcohol in the 30mL methylene dichloride, be reflected under this temperature and stirred 2 hours, solvent removed in vacuo, resistates stirs in the 100mL ether.Filtering solution, vacuum concentration, with flash chromatography (silica gel, 20: 1 hexanes: ethyl acetate) purifying obtains the 2-bromo-4 that polluted by carbon tetrabromide, the 5-difluoro benzyl bromide, it need not to be further purified and uses.Method with shown in the preparation of intermediate 2-4 is converted into title compound with bromotoluene.
LC/MS 394 and 396 (M+1).
Basically according to the method shown in the preparation method of intermediate 1-4, prepare the intermediate in the table 1.
Table 1
Intermediate R 3 Select 1H NMR data (CD 3OD)
5 2-F，4-Cl，5-F 7.11(dd，1H，J＝8.9，6.4Hz)，7.03(dd，1H，J＝9.0，6.6)
6 2-F，5-Cl 7.27(dd，1H，J＝6.4，2.5Hz)，7.21(m.1H)，7.03(t，1H，J ＝9.2Hz)
7 2-Me，5-Cl 7.16(d，1H，J＝1.8Hz)，7.11-7.07(m，2H)，2.34(s，3H)
8 2-Cl，5-Cl 7.34(d，1H，J＝9.0)，7.33(d，1H，J＝2.1Hz)，7.21(dd，1H，J ＝8.5，2.5Hz)
9 2-F，3-Cl，6-F 7.35(td，1H，J＝8.5，5.8Hz)，6.95(t，1H，J＝8.5Hz)
10 3-Cl，4-F 7.33(d，1H，J＝6.9Hz)，7.19-7.11(m，2H)
11 2-F，3-F，6-F 7.18-7.12(m，1H)，6.91(m，1H)
12 2-F，4-F，6-F 6.81(t，2H，J＝8.4Hz)
13 2-OCH 2Ph， 5-F 7.49(d，2H，J＝7.6Hz)，7.38(t，2H，J＝7.3Hz)，7.30(t，1H， J＝7.3Hz)，6.96- 6.89(m，3H)，5.11(d，1H，J＝11.7Hz)，5.08(d，1H，J＝11.9H z)
Intermediate 14
(3R, 7R)-3,7-dimethyl-1,4-Diazesuberane (diazepane)-2-ketone
Steps A: [(1R)-3-[methoxyl group (methyl) amino]-1-methyl-3-oxopropyl] the carboxylamine tertiary butyl ester
With (3R)-3-[(tert-butoxycarbonyl) amino] butyric acid (1g, 5mmol) 1-[3-(dimethylamino) propyl group of the solution in acetonitrile (40mL)]-3-ethyl-carbodiimide hydrochloride (EDC; 1.05g, 5.5mmol), I-hydroxybenzotriazole (HOBt; 810mg, 6mmol), N, the O-dimethyl hydroxylamine hydrochloride (1.0g, 10mmol) and triethylamine (1.4mL) handle, at room temperature stirred 2 days.Evaporating solns, resistates obtains the colourless toughening oil of required product with purified by flash chromatography in Biotage  system (silica gel, 40-90% ethyl acetate/hexane gradient).MS269.1(M+Na)。
Step B:[(1R)-and 1-methyl-3-oxopropyl] the carboxylamine tertiary butyl ester
Under-40 ℃ of nitrogen atmospheres, lithium aluminium hydride (5mL, 1.0MTHF solution) is slowly added [(1R)-3-[methoxyl group (methyl) amino]-1-methyl-3-oxopropyl] in the stirred solution of carboxylamine tertiary butyl ester in tetrahydrofuran (THF) (25mL).After 30 minutes, reaction mixture is removed cooling bath with the quenching of saturated aqueous ammonium chloride solution, continues to stir 1 hour.Mixture filters by C salt filter pad, washs with ether.Filtrate is used ice-cold 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and salt water washing successively, uses dried over mgso, and filtration and evaporation obtain the title compound water white oil.MS 87.9(M-Boc+1)。
Step C:N-[(3R)-and the 3-[tert-butoxycarbonyl] amino] butyl]-the D-alanine methyl ester
Will [(1R)-and 1-methyl-3-oxopropyl] carboxylamine tertiary butyl ester (0.75g, 3.65mmol) solution in ethanol (25mL) is with D-Beta Alanine methyl ester hydrochloride (0.5g, 3.57mmol), borine pyridine (0.5mL, 8M) and salt of wormwood (0.5g, 3.62mmol) handle, reaction mixture stirs and spends the night.Filter out the white precipitate that obtains,, need not to be further purified and be used for next step with chloroform washing, evaporated filtrate.MS 175.1(M-Boc+1)。
Step D:N-[(benzyloxy) carbonyl]-N-[(3R)-and the 3-[tert-butoxycarbonyl] amino] butyl]-the D-alanine methyl ester
The N-[(3R that obtains by above-mentioned steps)-and the 3-[tert-butoxycarbonyl] amino] butyl]-(0.99g 3.6mmol) handles the solution of D-alanine methyl ester in THF (30mL), at room temperature stirs and spends the night with N-benzyloxycarbonyl succinimide.Remove and desolvate, resistates obtains the title compound water white oil with purified by flash chromatography in Biotage  system (silica gel, 10-75% ethyl acetate/hexane gradient).MS431.1(M+Na)。
Step e: N-[(3R)-the amino butyl of 3-]-the N-[(benzyloxy) carbonyl]-the D-alanine methyl ester
With the N-[(benzyloxy) carbonyl]-N-[(3R)-and the 3-[tert-butoxycarbonyl] amino] butyl]-(0.75g 1.8mmol) at room temperature stirred 2 hours with 4N hydrochloric acid in two  alkane (10mL) the D-alanine methyl ester, evaporation.Resistates obtains required product water white oil with purified by flash chromatography in Biotage  system (silica gel, 8% methyl alcohol/2N hydrazine dichloride methane solution).MS309.1(M+1)。
Step F: (2R, 5R)-2,5-dimethyl-3-oxo-1,4-Diazesuberane-1-benzyl carboxylate
To N-[(3R)-the amino butyl of 3-]-the N-[(benzyloxy) carbonyl]-D-alanine methyl ester (0.5g, 1.6mmol) add trimethyl aluminium (0.8mL in the solution in methylene dichloride (65mL), the 2M toluene solution) and triethylamine (0.025mL, 0.16mmol), reaction mixture at room temperature stirs and spends the night.Add C salt, reaction is by dripping the quenching of saturated aqueous ammonium chloride solution.Filter out the white particle of formation, use washed with dichloromethane.Evaporated filtrate obtains title compound with purified by flash chromatography in Biotage  system (silica gel, 5% ethanol/methylene).MS277.2(M+1)。
Step G:(3R, 7R)-3,7-dimethyl-1,4-Diazesuberane-2-ketone
With (2R, 5R)-2,5-dimethyl-3-oxo-1,4-Diazesuberane-1-benzyl carboxylate (160mg) and the mixture of 10% palladium/carbon (32mg) in methyl alcohol (15mL) at room temperature stir and spend the night, filter by C salt, with 10% methanol wash in methylene dichloride.Filter concentrating under reduced pressure and obtain title compound.MS 143.1(M+1)。
Basically according to the described method of the preparation of above-mentioned intermediate 14, the intermediate in the table 2 is listed in preparation.
Table 2
Figure A20048002218400561
Intermediate R 4 R 6 MS(M+1)
15 2-pyridyl-CH 2 CH 3 220.2
16 H 2-F-phenyl-CH 2 223.2
17 CH 3 2-F-phenyl-CH 2 237.7
18 CH 3 CF 3 197.2
19 2-F-phenyl-CH 2 CH 3 237.2
20 CF 3CH 2 CH 3 211.2
21 2-Me-phenyl-CH 2 CH 3 233.2
22 2-CF 3-phenyl-CH 2 CH 3 287.3
Intermediate 23
Figure A20048002218400571
(3R, 6R)-six hydrogen-3,6-dimethyl-2H-1,4-diaza azepines-2-ketone
Steps A: the amino 3-[(tert-butoxycarbonyl)]-2 Methylpropionic acid
With di-t-butyl pyrocarbonate (22mL, 22mmol, 1M THF solution) be added in DL-3-aminoisobutyric acid in the water (30mL) (2.06g, 20mmol) and salt of wormwood (3.0g 22mmol), at room temperature stirs and spends the night.Aqueous mixture washs with ether, and with the careful acidifying under 0 ℃ of 3N hydrochloric acid, the turbid mixture that obtains extracts with ethyl acetate (3x) subsequently.Dried over sodium sulfate is used in the organic layer salt water washing that merges, and filtration and evaporation obtain the 3-[(tert-butoxycarbonyl) amino]-the 2 Methylpropionic acid white solid.
Step B:{3-[methoxyl group (methyl) amino]-2-methyl-3-oxopropyl } the carboxylamine tertiary butyl ester
With the 3-[(tert-butoxycarbonyl) amino]-2 Methylpropionic acid (2.0g 9.9mmol) is dissolved in the acetonitrile (50mL), to solution add HOBT (1.6g, 11.85mmol) and EDC (2.0g, 10.4mmol).Reaction was at room temperature stirred 2 hours, and (2.8mL, 20mmol) and N, (2.0g 20mmol) handles the O-dimethyl hydroxylamine hydrochloride to use triethylamine subsequently.Reaction mixture at room temperature stirs and spends the night, and the quenching of reaction water is extracted with ethyl acetate (3x).The organic extraction that merges is used 0.5N hydrochloric acid, 1N aqueous carbonic acid hydrogen sodium solution and salt water washing successively, uses dried over sodium sulfate, filters and evaporation.Crude product obtains with purified by flash chromatography in Biotage  system (silica gel, the 40-100% ethyl acetate in hexane): 3-[methoxyl group (methyl) amino]-2-methyl-3-oxopropyl } carboxylamine tertiary butyl ester white solid.MS(M+1-Boc)：147。
Step C:(2-methyl-3-oxopropyl) carboxylamine tertiary butyl ester
In-40 ℃ of nitrogen atmospheres, in about 15 minutes with LAH (10mL, 10mmol, 1M THF solution) solution slowly adds: 3-[methoxyl group (methyl) amino]-2-methyl-3-oxopropyl } (2.2g is 8.9mmol) in the stirred solution in THF (40mL) for the carboxylamine tertiary butyl ester.After 30 minutes, reaction mixture at room temperature stirred 1 hour by dripping the quenching of saturated aqueous sodium sulfite solution-40 ℃ of stirrings.Mixture filters by C salt, and filtrate is used ice-cold 1N hydrochloric acid (2x), saturated aqueous sodium bicarbonate and salt water washing successively, uses dried over mgso, filters and concentrate to obtain (2-methyl-3-oxopropyl) colourless toughening oil of carboxylamine tertiary butyl ester.
MS(M+1-Boc)：88.0。
Step D:N-{3-[(tert-butoxycarbonyl) amino]-the 2-methyl-propyl }-the D-alanine methyl ester
To (2-methyl-3-oxopropyl) carboxylamine tertiary butyl ester (2.0g, 8.9mmol) add in the stirred solution in ethanol D-alanine methyl ester hydrochloride (1.25g, 8.9mmol), add subsequently salt of wormwood (0.62g, 4.5mmol).The mixture that obtains at room temperature stirred 3 hours, once add sodium cyanoborohydride (0.63g, 10mmol).Reaction mixture at room temperature stirs and spends the night, and removes on rotatory evaporator and desolvates, and resistates is dissolved in the water, extracts with ethyl acetate (3x).Dried over sodium sulfate is used in the organic extraction salt water washing that merges, and evaporation obtains the N-{3-[(tert-butoxycarbonyl) amino]-the 2-methyl-propyl }-the colourless toughening oil of D-alanine methyl ester, it need not to be further purified and uses.MS(M+1-Boc)：175.3。
Step e: the carbonyl N-[(benzyloxy)]-the N-{3-[(tert-butoxycarbonyl) amino]-the 2-methyl-propyl }-the D-alanine methyl ester
To the N-{3-[(tert-butoxycarbonyl) amino]-the 2-methyl-propyl-add in the stirred solution of D-alanine methyl ester (2.5g, about 8.9mmol) in methylene dichloride (50mL) Cbz-OSu (2.25g, 9.0mmol).The mixture that obtains at room temperature stirred 3 days, remove with rotatory evaporator and to desolvate, crude product obtains the N-[(benzyloxy with purified by flash chromatography in Biotage  system (silica gel, the 25-80% ethyl acetate in hexane)) carbonyl]-the N-{3-[(tert-butoxycarbonyl) amino]-the 2-methyl-propyl }-the colourless toughening oil of D-alanine methyl ester.MS(M+1-Boc)：309.4。
Step F: N-(3-amino-2-methyl propyl group)-N-[(benzyloxy) carbonyl]-the D-alanine methyl ester
The N-[(benzyloxy) carbonyl]-the N-{3-[(tert-butoxycarbonyl) amino]-the 2-methyl-propyl }-(1.6g 3.9mmol) at room temperature is used in 4N salt acid treatment 2 hours in the two  alkane (10mL) to the D-alanine methyl ester.Under nitrogen gas stream, remove and desolvate, crude product obtains N-(3-amino-2-methyl propyl group)-N-[(benzyloxy with purified by flash chromatography in Biotage  system (silica gel, the methyl alcohol of 7% premixed 2N ammonia/in methylene dichloride)) carbonyl]-the colourless toughening oil of D-alanine methyl ester.MS(M+1)：309.4。
Step G:(2R, 6S)-six hydrogen-2,6-dimethyl-3-oxo-1H-1,4-diaza azepines-1-benzyl carboxylate and (2R, 6R)-six hydrogen-2,6-dimethyl-3-oxo-1H-1,4-diaza azepines-1-benzyl carboxylate
To N-(3-amino-2-methyl propyl group)-N-[(benzyloxy) carbonyl]-D-alanine methyl ester (0.6g, 2.0mmol) add the 2M solution (1.0mL of tertiary butyl chlorination magnesium in ether in the stirred solution in methylene dichloride (60mL), 2mmol), be reflected under the nitrogen atmosphere at room temperature to stir and spend the night.(1mL, 2mmol), reaction continues one day again, subsequently by adding C salt, adds saturated aqueous sodium sulfate subsequently and gathers cold to add more azoviolets.Mixture stirred 30 minutes, filtered the filtrate evaporation.Crude product Biotage  system (silica gel, the ethyl acetate of 60-100% in hexane) obtain two diastereomers with purified by flash chromatography in: (the 2R of very fast wash-out, 6S)-six hydrogen-2,6-dimethyl-3-oxo-1H-1, (the 2S of 4-diaza azepines-1-benzyl carboxylate and slow wash-out, 6R)-six hydrogen-2,6-dimethyl-3-oxo-1H-1,4-diaza azepines-1-benzyl carboxylate.MS (M+1): 277.3; 277.3 (separately).
Step H:(3R, 6R)-six hydrogen-3,6-dimethyl-2H-1,4-diaza azepines-2-ketone
Under hydrogen balloon will (2R, 6S)-six hydrogen-2,6-dimethyl-3-oxo-1H-1,4-diaza azepines-1-benzyl carboxylate (220mg, 0.8mmol) make catalyzer with Pd/C (30mg) and at room temperature stir and spend the night by the solution in ethanol (10mL).Remove by filter catalyzer through C salt, be used in 10% methanol wash in the methylene dichloride.Removing desolvates obtains (3R, 6R)-six hydrogen-3,6-dimethyl-2H-1,4-diaza azepines-2-ketone white crystalline solid.MS(M+1)：143.1。
The method preparation that this intermediate is described with similar substantially synthetic intermediate 23 in table 3.
Table 3
Intermediate R 4 R 8 MS(M+1)
24 Me (S)-Me 143
25 Et (R)-Me 157
26 Et (S)-Me 157
27 CH 2CF 3 (R)-Me 211
28 CH 2CF 3 (S)-Me 211
Intermediate 29
(9aR)-4-methyl octahydro-5H-pyrrolo-[1,2-d] [1,4] diaza azepines-5-ketone
Steps A: [(2R)-and 1-(carbonyl tert.-butoxy) tetramethyleneimine-2-yl] acetonitrile
To (R)-N-Boc-Prolinol (4.33g, 20mmol) add in the stirred solution in methylene dichloride (100mL) triethylamine (3.4mL, 24mmol), 4-dimethylaminopyridine (250mg, 2mmol) and Tosyl chloride (4.0g, 20mmol).Solution at room temperature stirred 24 hours, used cold (0 ℃) 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and salt water washing successively.The organic layer anhydrous sodium sulfate drying concentrates and obtains the thickness yellow oil.The product that obtains thus is dissolved in N, in the dinethylformamide (40mL), at room temperature stirred 7 days, between ethyl acetate and 1N aqueous carbonic acid hydrogen sodium solution, distribute subsequently with sodium cyanide.After the processing of conventional water, crude product obtains [(2R)-1-(carbonyl tert.-butoxy) tetramethyleneimine-2-yl] acetonitrile light yellow oil with purified by flash chromatography in Biotage  system (silica gel, the gradient 5-60% ethyl acetate in hexane).
Step B:[(2R)-and 1-pyruvoyl tetramethyleneimine-2-yl] acetonitrile
Will [(2R)-1-(carbonyl tert.-butoxy) tetramethyleneimine-2-yl] acetonitrile (1.0g, 4.75mmol) (1: 1 mixture at room temperature stirred 3 hours in 12mL) at TFA and methylene dichloride.Removal of solvent under reduced pressure, resistates are dissolved in the acetonitrile (25mL), add pyruvic acid (450mg in this solution, 5.0mmol), add subsequently HOBT (0.8g, 6mmol), EDC (1.0g, 5.5mmol) and triethylamine (1.0mL, 7.0mmol), reaction is at room temperature stirred and is spent the night.Remove desolvate after, crude product obtains [(2R)-1-pyruvoyl tetramethyleneimine-2-yl] acetonitrile with purified by flash chromatography in Biotage  system (silica gel, the 30-90% ethyl acetate in hexane).MS(M+Na)：203.2。
Step C:(9aR)-4-methyl octahydro-5H-pyrrolo-[1,2-d] [1,4] diaza azepines-5-ketone
Will [(2R)-and 1-pyruvoyl tetramethyleneimine-2-yl] (250mg 1.38mmol) is dissolved in the ethanol acetonitrile, is reflected under the hydrogen balloon at room temperature to stir 3 days in the presence of platinum oxide (25mg) and chloroform (0.25mL).Filter out catalyzer with C salt, with 10% methanol wash in methylene dichloride.The organic layer that evaporation merges, crude product is at Biotage  system (silica gel, the ethyl acetate of 5-60% in hexane) obtain non-enantiomer mixture 4-methyl octahydro-5H-pyrrolo-[1,2-d] [1,4] diaza azepines-5-ketone light yellow oil with purified by flash chromatography in.MS(M+1-Boc)：169.2。
Embodiment 1
(3R, 7R)-4-[(3R)-3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-3,7-dimethyl-1,4-Diazesuberane-2-ketone
Steps A: (3R, 7R)-4-[(3R)-the 3[(tert-butoxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-3,7-dimethyl-1,4-Diazesuberane-2-ketone
At-20 to-30 ℃ with chloroformic acid isobutyl (0.085mL, 0.63mmol) adding (3R)-3[(tert-butoxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid (intermediate 3,210mg, 0.63mmol) and N-methylmorpholine (0.080mL, 0.7mmol) in the solution in the 10mL methylene dichloride, the mixture stirring that obtains 1 hour.In above-mentioned solution, add (3R, 7R)-3,7-dimethyl-1, the solution of 4-Diazesuberane-2-ketone in methylene dichloride (5mL), reaction mixture is warming to room temperature, and lasting stirring is spent the night.Solution is directly used Biotage  system (silica gel, gradient 5% ethanol/methylene) to carry out flash chromatography and is obtained the title compound white solid.MS 358(M-Boc+1)。
Step B:(3R, 7R)-4-[(3R)-3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-3,7-dimethyl-1,4-Diazesuberane-2-ketone, hydrochloride
Will (3R, 7R)-4-[(3R)-the 3[(tert-butoxycarbonyl) amino]-4-(2,4; the 5-trifluorophenyl) butyryl radicals]-3,7-dimethyl-1,4-Diazesuberane-2-ketone (175mg; 0.38mmol) (4mL 4N) stirred 2 hours, concentrated for solution in the 4N hydrochloric acid of 4mL in two  alkane.Resistates dried overnight under vacuum obtains the title compound white solid.MS 358.2(M+1)。
Basically according to embodiment 1 described method, prepare the embodiment that in table 4, lists.
Table 4
Embodiment R 1 R 4 R 6 MS(M+1)
2 2-F，4-F，5-F 2-pyridyl-CH 2 CH 3 435.2
3 2-F，4-F，5-F H 2-F-phenyl-CH 2 438.3
4 2-F，4-F，5-F CH 3 2-F-phenyl-CH 2 452.3
5 2-F，4-F，5-F CH 3 CF 3 412.3
6 2-F，4-F，5-F 2-F-phenyl-CH 2 CH 3 452.3
7 2-F，4-F，5-F CF 3CH 2 CH 3 426.3
8 2-F，4-F，5-F 2-Me-phenyl-CH 2 CH 3 448.3
9 2-F，4-F，5-F 2-CF 3-phenyl-CH 2 CH 3 502.4
Embodiment 10
(3R, 6S)-4-[(3R)-3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals] six hydrogen-3,6-dimethyl-2H-1,4-diaza azepines-2-ketone
Steps A: (3R, 6S)-4[(3R)-the 3-[(tert-butoxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-3,6-dimethyl-2H-1,4-diaza azepines-2-ketone
To (3R)-3-[(tert-butoxycarbonyl) amino]-4-(2,4, the 5-trifluorophenyl) butyric acid (intermediate 3,120mg, 0.36mmol) add in the stirred solution in acetonitrile (10mL) HOBT (60mg, 0.43mmol) and EDC (75mg, 0.4mmol).Reaction was at room temperature stirred 1 hour, with (3R, 6R)-six hydrogen-3,6-dimethyl-2H-1, (intermediate 23,50mg 0.35mmol) handle 4-diaza azepines-2-ketone.Reaction is at room temperature stirred and is spent the night, and removes and desolvates, and crude product obtains the title compound white solid with purified by flash chromatography in Biotage  system (silica gel, 6% methyl alcohol in methylene dichloride).MS(M+1-Boc)：358.0。
Step B:(3R, 6S)-4-[(3R)-3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals] six hydrogen-3,6-dimethyl-2H-1,4-diaza azepines-2-keto hydrochloride
At room temperature be used in 4N salt acid treatment in the two  alkane (2mL) (3R, 6S)-4[(3R)-3-[(tert-butoxycarbonyl) amino]-4-(2,4; the 5-trifluorophenyl) butyryl radicals]-3; 6-dimethyl-2H-1,4-diaza azepines-2-ketone (135mg, 0.3mmol) 2 hours.Remove in nitrogen gas stream and desolvate, crude product obtains the title compound white solid with purified by flash chromatography in Biotage  system (silica gel, the methyl alcohol of 20%2N ammonia/in methylene dichloride).MS(M+1)：358.2。
Basically be prepared as follows embodiment according to the embodiment 10 synthetic middle similar approach of describing.
Table 5
Figure A20048002218400641
Embodiment R 4 R 8 MS(M+1)
11 Me (R)-Me 358.1
12 Et (S)-Me 372.0
13 Et (R)-Me 372.1
14 CH 2CF 3 (S)-Me 425.9
15 CH 2CF 3 (R)-Me 425.9
Embodiment 16
(4R, 9aR)-3-[(3R)-3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-4-methyl octahydro-5H-pyrrolo-[1,2d]-[1,4] diaza azepines-5-ketone
According to the synthetic described method of embodiment 10, by intermediate 29 preparation title compounds.Before deprotection, separate two diastereomers with ChiralCell OD post, be used in 10% ethanol elution in the hexane.The diastereomer of the slow wash-out of processing [(1R)-3-[(4R, 9aR)-4-methyl-5-oxo octahydro-3H-pyrrolo-[1,2-d] [1,4] diaza azepines-3-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl) propyl group] the carboxylamine tertiary butyl ester becomes final product.MS(M+1)：384.4。
The embodiment of pharmaceutical preparation
Specific embodiments as combination of oral medication, the tablet of 100mg dosage is made up of 100mg arbitrary compound of the present invention, 268mg Microcrystalline Cellulose, 20mg croscarmellose sodium and 4mg Magnesium Stearate, at first mixed active composition, Microcrystalline Cellulose and croscarmellose, lubricated with Magnesium Stearate subsequently, be pressed into tablet.
Although describe and for example understand the present invention, it will be appreciated by those skilled in the art that various corrections, change, the modification that to carry out ways and means, substitute, deletion or add and without prejudice to the spirit and scope of the present invention with reference to its some specific embodiments.For example, because the Mammals of being treated can be used the effective dose except that concrete dosage as herein described to the result of the variation of the response of the arbitrary symptom of compounds for treating of the invention described above.According to according to selected concrete active compound or do not have pharmaceutical carrier and dosage form that is adopted and administering mode, the response of science of observed particular drug can change, and the variation of this expected result or difference are targets of the present invention and put into practice desired.Therefore, the invention is intended to the scope definition by appending claims, these claims are reasonable dismissal broadly.

Claims (34)

1, the compound of formula I:
Or its pharmaceutically useful salt; Wherein
N is respectively 0,1 or 2;
Ar is by 1-5 R 3The phenyl that substituting group replaces;
R 1Be selected from following group:
H；
C 1-10Alkyl, wherein alkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, CN, hydroxyl, R respectively by 1-5 2, OR 2, NHSO 2R 2, NR 2SO 2R 2, SO 2R 2, CO 2H and C 1-6The substituting group of alkoxy carbonyl replaces;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heterocyclic radical, wherein heterocyclic radical is unsubstituted or is selected from oxo, hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen;
Each R 3Be selected from following group respectively:
H；
Halogen;
Cyano group;
Hydroxyl;
C 1-6Alkyl is unsubstituted or replaced by 1-5 halogen;
C 1-6Alkoxyl group is unsubstituted or replaced by 1-5 halogen;
Carboxyl;
Alkoxy carbonyl;
Amino;
NHR 2；
NR 2R 2；
NHSO 2R 2；
NR 2SO 2R 2；
NHCOR 2；
NR 2COR 2；
NHCO 2R 2；
NR 2CO 2R 2；
SO 2R 2；
SO 2NH 2；
SO 2NHR 2With
SO 2NR 2R 2；
Each R 2Be respectively C 1-6Alkyl, it is unsubstituted or is selected from halogen, CO respectively by 1-5 2H and C 1-6The substituting group of alkoxy carbonyl replaces;
R 4, R 6And R 10Be selected from following group respectively:
H；
Cyano group;
Carboxyl;
C 1-6Alkoxy carbonyl;
C 1-10Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heterocyclic radical, wherein heterocyclic radical is unsubstituted or is selected from oxo, hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) nCONR 12R 13, R wherein 12And R 13Be selected from H, tetrazyl, thiazolyl, (CH respectively 2) n-phenyl, (CH 2) n-C 3-6Cycloalkyl and C 1-6Alkyl, wherein alkyl is unsubstituted or is replaced by 1-5 halogen, wherein phenyl and cycloalkyl are unsubstituted or are selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; Or R wherein 12And R 13Be connected to form heterocycle with the nitrogen-atoms that links to each other with them, it is selected from azetidine, tetramethyleneimine, piperidines, piperazine and morpholine, and wherein said heterocycle is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen;
R 8Be to be selected from halogen, hydroxyl and R 4Group;
R 5, R 7And R 11Be selected from H or C respectively 1-6Alkyl; Or R wherein 7And R 1With and R 1The nitrogen-atoms that links to each other is connected to form heterocycle together, and it is selected from azetidine, tetramethyleneimine and piperidines, and wherein said heterocycle is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
R 9Be to be selected from H, hydroxyl, halogen or C 1-6The group of alkyl;
Its prerequisite is R 6, R 7, R 8And R 9Be not H one of at least.
2, the compound of the claim 1 of formula Ia:
Figure A2004800221840005C1
Wherein has the R configuration with the * marked carbon atoms.
3, the compound of claim 1, wherein R 3It is the group that is selected from H, fluorine, chlorine, bromine, trifluoromethyl and methyl.
4, the compound of claim 3, wherein R 3Be H, fluorine or chlorine.
5, the compound of claim 1, wherein R 1Be selected from following group:
H；
C 1-6Alkyl, wherein alkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement; With
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
6. the compound of claim 5, wherein R 1Be to be selected from H, methyl and cyclopropyl.
7, the compound of claim 5, wherein R 1Be H.
8, the compound of claim 1, wherein R 4Be to be selected from:
H；
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
9, the compound of claim 8, wherein R 4Be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph)。
10, the compound of claim 1, wherein R 6Be selected from following group:
H；
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-heteroaryl, wherein heteroaryl is unsubstituted or is selected from hydroxyl, halogen, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement;
(CH 2) n-C 3-6Cycloalkyl, wherein cycloalkyl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-3 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
11, the compound of claim 10, wherein R 6Be selected from following group:
H；
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement;
(CH 2) n-aryl, wherein aryl is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement; With
Wherein at (CH 2) nIn any methylene radical (CH 2) be unsubstituted or be selected from halogen, hydroxyl and C respectively by 1-2 1-4The substituting group of alkyl replaces, C 1-4Alkyl is unsubstituted or is replaced by 1-5 halogen.
12, the compound of claim 11, R 6Be selected from following group:
H；
CH 3；
CH 2CH 3；
CF 3；
CH 2Ph; With
CH 2(2-F-Ph)。
13, the compound of claim 1, wherein R 8Be to be selected from following group:
H；
Hydroxyl;
Halogen; With
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement.
14, the compound of claim 13, wherein R 8Be H.
15, the compound of claim 1, wherein R 10Be to be selected from following group:
H; With
C 1-6Alkyl, it is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkoxyl group, carboxyl, C 1-6Alkoxy carbonyl and phenyl-C 1-3The substituting group of alkoxyl group replaces, and wherein alkoxyl group is unsubstituted or by 1-5 halogen replacement.
16, the compound of claim 15, wherein R 10Be H.
17, the compound of claim 1, wherein R 5, R 7And R 11Be selected from H and methyl respectively.
18, the compound of claim 17, wherein R 5, R 7And R 11Be H.
19, the compound of claim 1, wherein R 9Be selected from H, halogen and methyl.
20, the compound of claim 19, wherein R 9Be H.
21, the compound of claim 19, wherein R 9Be methyl and R 5, R 7, R 8, R 10And R 11Be H.
22, the compound of claim 21, wherein R 4Be to be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph)。
23, the compound of claim 1, wherein R 5, R 7, R 8, R 9, R 10And R 11Be H, its prerequisite is R 6Not H.
24, the compound of claim 23, wherein R 4Be to be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph); With
R 6Be to be selected from following group:
CH 3；
CH 2CH 3；
CF 3；
CH 2Ph; With
CH 2(2-F-Ph)。
25, the compound of claim 24, wherein R 1Be H.
26, the compound of claim 25, wherein the three-dimensional carbon atom with * * and * * * mark has the stereochemistry of representing in formula Ib:
27, the compound of claim 1, wherein R 7And R 1With and R 1The nitrogen-atoms that links to each other is connected to form heterocycle together, and it is selected from azetidine, tetramethyleneimine and piperidines, and wherein said heterocycle is unsubstituted or is selected from halogen, hydroxyl, C respectively by 1-5 1-6Alkyl and C 1-6The substituting group of alkoxyl group replaces, and wherein alkyl and alkoxyl group are unsubstituted or by 1-5 halogen replacement.
28, the compound of claim 27, wherein R 7And R 1With and R 1The nitrogen-atoms that links to each other is connected to form pyrrolidine ring together.
29, the compound of claim 28, wherein R 4Be to be selected from following group:
H；
CH 3；
CH 2CH 3；
CH 2CF 3；
CH 2(2-pyridyl);
CH 2Ph；
CH 2(2-F-Ph)；
CH 2(2-Me-Ph); With
CH 2(2-CF 3-Ph)。
30, compound, it is selected from following group:
Figure A2004800221840011C1
Or its pharmaceutically useful salt.
31, pharmaceutical composition, it contains the compound and the pharmaceutically useful carrier of claim 1.
32, the compound of claim 1 is used for being selected from purposes in the medicine of symptom of hyperglycemia, type ii diabetes, obesity and lipoid dyscrasias in Mammals treatment in production.
33, the purposes of claim 32, wherein said lipoid dyscrasias are selected from hyperlipemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL.
34, the pharmaceutical composition of claim 31, it additionally contains metformin.
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